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How are neuromodulator receptors distributed?

How are neuromodulator receptors distributed?


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Irrespective of where, when and how neuromodulators are released, eventually they are detected by some receptors in the membrane of a target neuron (typically G protein-coupled receptors)

Neurotransmitter receptors are typically distributed on the dendrite and the soma of a neuron (and only occasionally on the axon):

  • at excitatory synapses (more distal)
  • at inhibibitory synapses (more proximal)

Does this rule of thumb also hold for neuromodulator receptors:

  • excitatory → more distal
  • inhibitory → more proximal

And are they clustered (like ligand-gated ion channels at synapses)?


How are neuromodulator receptors distributed? - Biology

When I started this page, I was trying to answer the question :
"Where are the neuromodulator receptors located? Are they inside the synaptic cleft or outside it?".
Although I've not yet read all the papers whose links I've collected, it's pretty clear that the neuromodulator receptors are located outside the synaptic cleft. This has particular significance for
CRH Receptor and
CRH & Serotonin .

Searching Google for "neuromodulator receptors" yielded 2,460,000 hits.

None of the titles of the possibly relevant hits from the first four pages mentioned the location of the synapse, but the abstracts or articles themselves might:


The laminar distributions and postnatal development of neuromodulator and neurotransmitter receptors in the cat visual cortex (Goog) - 1986

Only abstract available online.


Differential Distribution of Functional Receptors for Neuromodulators Evoking Short-Term Heterosynaptic Plasticity in Aplysia Sensory Neurons (Goog) - 1996

Full length PDF available online for free.


Neuromodulation and Neural Plasticity (Goog) - 1998

Short student paper.
Possible new search terms: " neuromodulatory synapse
".
" Neuromodulation of the postsynaptic neuron depends not so much on the neurotransmitter as on the receptor to which it binds, called a metabotropic receptor.
"
" Whereas facilitation is an increase in postsynaptic activity accompanied by increased neuromodulator transmission, habituation is a reduction in postsynaptic response accompanied by reduced neurotransmitter release from the presynaptic neuron.
"
My comment:
At least one reference which might be interesting.

Regulation of Neuromodulator Receptor Efficacy- Implications for Whole-Neuron and Synaptic Plasticity (Goog) - 2003

Full length PDF available online for free.


Neuromodulators control the polarity of spike-timing-Dependent Synaptic Plasticity (Goog) - 2007

Full length HTML available online for free.

Neuron - Pull-Push Neuromodulation of LTP and LTD Enables Bidirectional Experience-Induced Synaptic Scaling in Visual Cortex (Goog) - 2012

Searching Google for "neuromodulator receptors synapse" yielded 1,440,000 hits.

Many were repeats of those listed above. The new possibilities were:

Differential regulation of neocortical synapses by neuromodulators and activity (Goog) - 1997

Only abstract available online.
" Synapses are continually regulated by chemical modulators and by their own activity.
We tested the specificity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which mediate the recombination of cortical information.
Frequency-sensitive depression was much stronger in TC synapses than in IC synapses.

The two synapse types were differentially sensitive to presynaptic neuromodulators: only IC synapses were suppressed by activation of GABA(B) receptors, only TC synapses were enhanced by nicotinic acetylcholine receptors, and
muscarinic acetylcholine receptors suppressed both synapse types.
"
My comments:
1. Although not stated explicitly, this sounds as though the receptors are outside the synapse.
2. This article had many "Related citations" and "Cited by's" that I should probably look at.

Neuromodulation of Hippocampal Plasticity, Memory and Learning by Noradreniline (Goog) - 2007

Full length PDF available online for free.


Stephen Nurrish Research Group (Goog) - 2011

Many very good diagrams, but I wasn't able to copy and paste.
Distinguished between:
1. "Classical Synaptic" Transmission
2. Local Neuromodulation
3. Extrasynaptic "ectopic" Neuromodulation

So now I have a new search term: "Extrasynaptic Neuromodulation"

I left a friendly message in his comments box.
"Thanks for your post. I have a page you might find interesting:
Children of the Amphioxus
<http://sites.google.com/site/childrenoftheamphioxus/>
I cited your page at: Boys without Fathers, an endocrine hypothesis
<https://sites.google.com/site/boyswithoutfathers/home/neuromodulator-receptors>"

Searching Google for "Extrasynaptic Neuromodulation" yielded 30,500 hits.

Extrasynaptic-GABA-mediated neuromodulation in a sensory cortical neural network (Goog) - 2008

Tactile Communication and Neurorehabilitation Lab (Goog) - 2011

A very brief description of the lab's work.
"Neuromodulation is the process where nervous system activity is regulated (increased, decreased, sensitized, desensitized) by several classes of neurotransmitter chemicals called neuromodulators, including serotonin, dopamine, acetylcholine, histamine, etc.
Neuromodulator chemicals exist not only in the nerve cells (neurons) themselves but in the intercellular chemical "soup" in between the neurons. This intracellular chemistry can therefore act on large groups of neurons at a time. This mass extrasynaptic communication is different from synaptic communication between individual neurons.
"

Neuromodulation and G-Protein Coupled (metabotropic) Receptors (Goog) - undated

Online class covering a wide range of topics. Although I was able to copy the text after downloading the document, I was never able to copy any of the very good graphics. Worth another look.
The two statements that most intereste me are:
1. Postsynaptic GABAB Receptors are located outside of the synaptic cleft. They are Extrasynaptic.
2. As is the case for GABABRs, mGLURs appear to be located outside
of the synaptic cleft: they are extrasynaptic.
My comment:
It just occurred to me. Perhaps the terms "presynaptic receptor" and "postsynaptic receptor" may have always referred to receptors which are extrasynaptic and I just didn't realize it.
Additional comment subsequent to further reading:
After further study, I've decided that the above comment is mistaken. Although researchers are notoriously inconsistent in their use of terms,
they seem to often use the term "postsynaptic receptor" to refer to receptors within and on the postsynaptic side of the synaptic cleft, even though that isn't the way the term is being used here. However, it would seem that the term "presynaptic receptor" probably always refers to receptors which are extrasynaptic.

Searching Google for "presynaptic postsynaptic extrasynaptic" yielded 130,000 hits.

Searching Google for "presynaptic postsynaptic extrasynaptic receptors" yielded 67,300 hits.

Synaptic Transmission: Spillover in the Spotlight (Goog) - 2000

Full length PDF available online for free.
Must download to copy and paste.
from the abstract
"Fast neurotransmission in the brain is typically mediated by local actions of transmitters at ionotropic receptors within synaptic contacts. Recent studies now reveal that, in addition to point-to-point signaling,
amino-acid transmitters mediate diffuse signaling at extrasynaptic metabotropic receptors."
My comment:
Although it doesn't say so explicitly, the above could be interpreted to mean that all
ionotropic receptors are within synapses and all metabotropic receptors are extrasynaptic .
from the PDF
"In the mammalian brain, excitatory and inhibitory neurotransmission are mediated by the transmitters glutamate and g-aminobutyric acid (GABA), respectively.
Fast signaling between neurons occurs at specialized synaptic contacts formed between the axons of presynaptic cells and the soma or dendrites of postsynaptic target neurons."
My comment:
This makes it sound as though all '
excitatory and inhibitory neurotransmission are mediated by the transmitters glutamate and g-aminobutyric acid (GABA) ' exclusively. I will be surprised if that turns out to be the case.
more from the PDF
"The lifetime of transmitter action . is governed by a combination of diffusion . and uptake . by specific transporters in . glial membranes."
My comment:
Since the glia are outside the synapse, this implies that at least some of the transmitter which is released within the synaptic cleft leaves it.
more from the PDF
"This anatomical arrangement is optimal for rapid, point-to-point
signaling that occurs on the millisecond timescale. However, several recent studies [1–3] have now provided evidence that both GABA and glutamate mediate diffuse signaling at sites that are remote from synaptic contacts."
My comment:
I guess I need to look at these references. They are:
1. Scanziani M: GABA spillover activates postsynaptic GABAB
receptors to control rhythmic hippocampal activity.
Neuron 2000, 25:673-681.
2. Semyanov A, Kullmann DM: Modulation of GABAergic signaling
among interneurons by metabotropic glutamate receptors.
Neuron 2000, 25:663-672.
3. Mitchell SJ, Silver RA: Glutamate spillover suppresses inhibition by
activating presynaptic mGluRs. Nature 2000, 404:498-502.

more from the PDF
"Thus, GABA ‘spillover’ underlies both the presynaptic and postsynaptic activation of GABAB receptors."
"The simplest interpretation is that mGluRs are not present in
the synaptic cleft, rather they are located at a site on the nerve terminal away from the site of transmitter release (Figure 1). To activate perisynaptic mGluRs, glutamate must spread outside the synaptic cleft.
A common conclusion in all of these studies is that extrasynaptic, G-protein-coupled receptors provide a mechanism for sensing global activity in neural circuits."

more from the PDF
Very good diagram.
It's a little bit hard to read, but well worth the effort.


Presynaptic, extrasynaptic, axonal GABAa receptors in the CNS: where and why? (Goog) - 2005

Extrasynaptic and Postsynaptic Receptors in Glycinergic and GABAergic Neurotransmission: A Division of Labor? (Goog) - 2008

Modulation of Transmitter Release Via Presynaptic Ligand-Gated Ion
Channels (Goog) - 2008

GABAB receptors: structure, functions and clinical implications (Goog) - 2012

Only abstract available online.
"γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and has a key role in modulating neuronal activity.
GABA mediates its action via 2 classes of receptors, ionotropic GABAA and GABAC and metabotropic GABAB receptors.
Unlike GABAA and C receptors, which form chloride channels and are involved in fast synaptic inhibition, GABAB receptors are guanine nucleotide-binding (G) protein-coupled receptors that modulate calcium (Ca2+) and potassium (K+) channels and elicit both presynaptic and slow postsynaptic inhibition.
GABAB receptors are broadly expressed in the nervous system, modulating synaptic excitability and plasticity in the cerebral cortex, generating rhythmic activity in cortical and thalamic circuits, relaying primary afferent input to the spinal cord and brainstem, and affecting the activity of dopaminergic and other monoaminergic neurons.
"
My comment:
This is an interesting overview of GABA, but it doesn't say anything about the location of the receptors.


How are neuromodulator receptors distributed? - Biology

Membrane receptors for neuromodulators (NM) are highly regulated in their distribution and efficacy - a phenomenon which influences the individual cell's response to central signals of NM release. Even though NM receptor regulation is implicated in the pharmacological action of many drugs, and is also known to be influenced by various environmental factors, its functional consequences and modes of action are not well understood. In this paper we summarize relevant experimental evidence on NM receptor regulation (specifically dopamine D1 and D2 receptors) in order to explore its significance for neural and synaptic plasticity. We identify the relevant components of NM receptor regulation (receptor phosphorylation, receptor trafficking and sensitization of second-messenger pathways) gained from studies on cultured cells. Key principles in the regulation and control of short-term plasticity (sensitization) are identified, and a model is presented which employs direct and indirect feedback regulation of receptor efficacy. We also discuss long-term plasticity which involves shifts in receptor sensitivity and loss of responsivity to NM signals. Finally, we discuss the implications of NM receptor regulation for models of brain plasticity and memorization. We emphasize that a realistic model of brain plasticity will have to go beyond Hebbian models of long-term potentiation and depression. Plasticity in the distribution and efficacy of NM receptors may provide another important source of functional plasticity with implications for learning and memory.


Introduction

The term “trace amine” (TA) has been coined in the early 1970s by Alan Boulton and his colleagues to distinguish a group of endogenous vertebrate monoamines from their more abundant structural relatives, the catecholamine and indoleamine neurotransmitters (Boulton, 1974 Gainetdinov et al., 2018). TA are stored in nerve terminals with classical neurotransmitters such as dopamine (DOP), norepinephrine, or serotonin, and are released together with these classical neurotransmitters (Dewar et al., 1988 Premont et al., 2001). Despite their low abundance (Berry, 2004), there is evidence on the crucial physiological roles of TA in the neuromodulation of synaptic transmission in mammalian brains (Burchett and Hicks, 2006 Gainetdinov et al., 2018).

TA are produced by a wide range of organisms from bacteria to plants and vertebrates. In vertebrates, TA can be formed directly by the action of aromatic L-amino acid decarboxylase (AADC) on L-phenylalanine, L-tyrosine, and L-tryptophan, (Boulton and Wu, 1972 Saavedra, 1974 Silkaitis and Mosnaim, 1976 Dyck et al., 1983). TA production in bacteria has been mainly studied in food microorganisms, such as enterococci, lactobacilli, streptococci, lactococci, pediococci, and oenococci which represents the main producers of biogenic amines (Marcobal et al., 2006 Irsfeld et al., 2013 Williams et al., 2014 Barbieri et al., 2019).

Although there is some evidence on the low abundance of amine production in food-associated staphylococci (Rahmdel et al., 2018), the investigation of TA production in this genus has provided information about TA formation by the Staphylococcus species (Luqman et al., 2018). In this genus only some species are capable of TA production which can mainly be attributed to the presence of the gene sadA encoding staphylococcal aromatic amino acid decarboxylase. SadA decarboxylates tryptophan, tyrosine, and phenylalanine to tryptamine (TRY), tyramine (TYM), and phenethylamine (PEA), in a pyridoxalphosphate (PLP)-dependent reaction. It also decarboxylates dihydroxy phenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP) to the neurotransmitters DOP and serotonin (Luqman et al., 2018). TA producing staphylococci triggered the internalization into human colon adenocarcinoma cells by activation of the 㬒-adrenergic receptor (㬒-AR) (Luqman et al., 2018, 2019).

A study of the human intestinal microflora revealed that TA-producing staphylococci are present in the majority of human probands, suggesting a selective advantage. Moreover, a sadA deletion mutant of the animal pathogen Staphylococcus pseudintermedius showed a lower internalization rate than the parent strain in the presence of aromatic amino acids (AAAs). This may reinforce the hypothesis that the excreted TA interfere with host communication to improve the survival and colonization of the bacteria (Luqman et al., 2018, 2019). More recently it has been shown that TA-producing Staphylococcus epidermidis strains expressing SadA are predominant on human skin and that TA accelerate wound healing by antagonizing the 㬢-adrenergic receptor (㬢-AR) in keratinocytes (Luqman et al., 2020b).

In mammalians, TA are synthesized by aromatic L-amino acid decarboxylases (AADC EC 4.1.1.28) (Boulton and Wu, 1972 Snodgrass and Iversen, 1974 Silkaitis and Mosnaim, 1976 Dyck et al., 1983). Although AADC is widely accepted as the vertebrate synthetic enzyme for PEA, TYM, and TRY, the precursor amino acids are in fact extremely poor substrates for AADC (Christenson et al., 1970 Juorio and Yu, 1985 Gainetdinov et al., 2018). This raises the question whether the endogenous synthesis of TA plays a major role at all, or whether the uptake of TA from food and the production of TA by the microbiota are not as such decisive for exerting effects in mammalians. This assumption is supported by the relatively high concentrations of AAAs and TA present on human skin (10 and 5 μg/100 cm 2 , respectively) (Luqman et al., 2020b). Substantial TA concentrations have also been reported in the human gut in the decreasing order of TYM (from 7.6 to 621 μg g 𠄱 of stool sample, depending on the subject), DOP, TRY, serotonin, and PEA (Luqman et al., 2018). These relatively high TA levels on the skin and in the intestine indicate that they are not endogenous but can be of microbial origin.

The PLP-dependent Trp decarboxylases of the common gut Firmicutes Clostridium sporogenes and Ruminococcus gnavus have been enzymatically and structurally characterized (Williams et al., 2014). However, they assumed that such activities are extremely rare in bacteria. On the other hand, the staphylococcal aromatic amino acid decarboxylase, SadA, is a highly promiscuous enzyme. It decarboxylates all AAAs to TAs, and also dihydroxylated phenylalanine and 5-HTP to the neurotransmitters DOP and serotonin (Luqman et al., 2018). SadA producing staphylococci are prevalent in the gut and the human skin (Luqman et al., 2018, 2019, 2020b).

TA are neuromodulators that may have an impact on the well-being of mammals. Therefore, the answer to the question whether SadA is widespread in the human microbiome or whether it is an exotic exception in some Staphylococcus species, is of great importance. The metagenomic profiling of the microbiome allows the analysis of the phylogenetic distribution of individual genes. In this study we investigated the occurrence of SadA homologs in the human skin microbiome. We could show that the microbiome of each volunteer contained sadA homologous genes, with large variations from person to person. In addition, SadA homologs are widely distributed throughout almost the entire bacterial kingdom, especially among representatives of the human microbiota, suggesting that the skin microbiota may be able to produce significant amounts of TA to influence host signaling and physiology.


DISCUSSION

Animals, including insects, regulate their food intake to optimize growth and performance, and this regulation ensures that an animal consumes an optimal mixture of the required nutrients – the 'nutrient target' (Raubenheimer and Simpson, 1997 Raubenheimer and Simpson, 1999). In many insects, food selection involves detecting a desired food, initiating ingestion of that food, consuming the food and terminating the meal (Edgecomb et al., 1994). The selection of a particular food is a physiological complex process, influenced by sensory information (i.e. sight, smell and taste), previous ingestion experience, feedback from peripheral systems, such as stretch receptors in the gut, hormonal signals, blood composition and brain neurotransmitters, such as DA (Meguid et al., 2000 Wei et al., 2000).

Spiperone experiment. Effects of the dopamine antagonist spiperone (100 mmol l –1 in 1 μl of 100% ethanol) or control (1 μl of 100% ethanol) on Rhyparobia maderae nymph nutrient self-selection feeding behavior. Shown is the amount of sucrose and casein consumed by the cockroach nymphs with each treatment in addition to the total amount of food eaten. All values are means ± s.e.m. Significant differences between the treated group and the controls are indicated by asterisks:***P<0.001 (t-test) N=44 for the spiperone-injected cockroaches and N=40 for the ethanol-injected controls.

Spiperone experiment. Effects of the dopamine antagonist spiperone (100 mmol l –1 in 1 μl of 100% ethanol) or control (1 μl of 100% ethanol) on Rhyparobia maderae nymph nutrient self-selection feeding behavior. Shown is the amount of sucrose and casein consumed by the cockroach nymphs with each treatment in addition to the total amount of food eaten. All values are means ± s.e.m. Significant differences between the treated group and the controls are indicated by asterisks:***P<0.001 (t-test) N=44 for the spiperone-injected cockroaches and N=40 for the ethanol-injected controls.

Fig. 6. Motor activity experiment. Effects of 1 μl of 100% ethanol or control (1 μl of 0.7% NaCl) on motor activity in Rhyparobia maderae nymphs. Shown is the mean distance moved in 5 s (cm) at four time intervals. All values are means ± s.e.m. No statistically significant differences were observed between ethanol treatment and saline controls (repeated-measures ANOVA, P>0.05) or between the various time intervals (repeated-measures ANOVA, P>0.05). N=16 for saline-injected controls and N=14 for ethanol-injected nymphs.

Fig. 6. Motor activity experiment. Effects of 1 μl of 100% ethanol or control (1 μl of 0.7% NaCl) on motor activity in Rhyparobia maderae nymphs. Shown is the mean distance moved in 5 s (cm) at four time intervals. All values are means ± s.e.m. No statistically significant differences were observed between ethanol treatment and saline controls (repeated-measures ANOVA, P>0.05) or between the various time intervals (repeated-measures ANOVA, P>0.05). N=16 for saline-injected controls and N=14 for ethanol-injected nymphs.

In this study, when R. maderae nymphs were injected with 20 μl of 100 mmol l –1 DA, they showed a significant reduction in sucrose (83.3%) and total intake (78.9%) compared with saline-injected controls (Fig. 1). Although, not significant, nymphs injected with 20 μl of DA showed a 23% reduction in casein feeding compared with controls (Fig. 1). What was interesting was that administration of the DA receptor agonist 6,7-ADTN resulted in a significant feeding response at a lower dose than DA itself. Rhyparobia maderae nymphs injected with 1 μl of 100 mmol l –1 6,7-ADTN showed a significant reduction in sucrose (47.3%), casein (62%) and total food (48.3%) intake (Fig. 4). Neither DA nor 6,7-ADTN injections significantly affected percentage casein intake in R. maderae nymphs, providing evidence that the feeding reductions seen in nymphs injected with either DA or 6,7-ADTN occur for total food intake because casein:sucrose ratios were not affected. The balance of the macronutrients seems relatively stable in the face of changes in appetite in R. maderae nymphs.

So, why did 6,7-ADTN cause a significant response at a lower dose in our experiment? Experiments have shown that in the honeybee (Mustard et al., 2003) and cockroach brains (Orr et al., 1987), 6,7-ADTN actually stimulated DA receptors (as measured by cAMP production) at a level higher than that caused by DA when both were applied at the same concentration, suggesting that 6,7-ADTN is more potent at insect DA receptors than DA. The fact that 6,7-ADTN appears to be a more potent ligand at the insect DA receptor may explain why a higher dose of DA was needed to see significant feeding responses in our experiment.

The experiment with the DA antagonist chlorpromazine was conducted to determine an effective dose at eliciting a feeding response in R. maderae nymphs. Chlorpromazine was originally selected in this experiment because it is a known DA antagonist in vertebrates, and in the cockroach Nauphoeta cinerea chlorpromazine was found to be the most potent antagonist at DA receptors on salivary gland cells (Evans and Green, 1990). In addition, the lipophilic structure of chlorpromazine allows it to cross the blood–brain barrier easily (Martel et al., 1996). Surprisingly, higher doses of chlorpromazine (2 μl and 5 μl) in our experiment were lethal to R. maderae nymphs (Fig. 2). In contrast to the higher doses, nymphs injected with 1 μl of chlorpromazine did not differ significantly from controls in percentage mortality. Subsequently, this dose was used to determine if chlorpromazine had any effect on feeding behavior. Nymphs injected with 1 μl did not differ from controls in their sucrose, casein and total intake (Fig. 3). The two questions, then, are why did chlorpromazine cause mortality at higher doses, and why at the 1 μl dose was there no significant feeding response?

The simplest explanation is that chlorpromazine has been shown to bind to more receptor types than just DA. In insects, for example, chlorpromazine has been shown to bind to tyramine receptors, and has also been shown to act as an antagonist at insect OA receptors (Vanden Broeck et al., 1995 Blenau and Erber, 1998). In the salivary glands of the cockroach, Periplaneta americana, the 5-HT-induced secretory response was significantly reduced after treatment with chlorpromazine, suggesting that chlorpromazine may also act as a 5-HT receptor antagonist (Marg et al., 2004). The fact that chlorpromazine has the potential to inhibit so many receptor types, suggests that, at the higher doses used, more receptors were blocked in the nervous system of the R. maderae nymphs. Antagonizing multiple receptor types could have been the cause for the mortality in the groups that received the higher doses of chlorpromazine.

Although few R. maderae nymphs died from the 1 μl chlorpromazine injection, the drug still did not show any significant feeding response. It is possible that the group of nymphs injected with 1 μl also had more than one receptor type blocked (i.e. DA, OA, 5-HT) however, as the dose was lower, not as many receptors may have been occupied by chlorpromazine, thus causing the lower percentage mortality. This may also explain why there was not a significant feeding response seen with the 1 μl dose because blocking more than one type of receptor (i.e. OA, DA) could have caused all of these receptor systems to counteract each other. For example, OA antagonists have been shown to decrease feeding in R. maderae nymphs (Cohen et al., 2002) whereas in our experiments with the DA antagonist spiperone, R. maderae nymphs increased feeding (Fig. 5). Casein:sucrose ratios were statistically similar between the control nymphs and nymphs injected with 1 μl of chlorpromazine, suggesting that low doses of chlorpromazine do not affect R. maderae's ability to diet-mix.

In contrast to the chlorpromazine experiment, the DA antagonist spiperone caused a significant increase in feeding in both sucrose (75.6%) and total intake (70.3%) (Fig. 5). Casein feeding in R. maderae nymphs was also elevated (41.4%) but this was not statistically significant. The DA receptor antagonist spiperone has a higher affinity for the DA receptor compared with chlorpromazine (Degen et al., 2000). As spiperone has been shown to bind with higher affinity to DA receptors only, this may explain why spiperone showed a significant response where chlorpromazine did not. Both DA and the DA agonist 6,7-ADTN resulted in reduced feeding in R. maderae nymphs whereas the DA antagonist spiperone produced an increase in consumption, pointing to a role for DA in regulating feeding behavior in the R. maderae cockroach.

Another interesting observation in the spiperone experiment was that the R. maderae control nymphs injected with 100% ethanol consumed a much lower amount of sucrose compared with the control nymphs (injected with insect saline) in the other experiments. Control nymphs in the other experiments consumed ∼17 mg of sucrose whereas in this experiment, R. maderae consumed less than 4 mg. Total feeding in the ethanol-injected control nymphs was much lower (∼5 mg) compared with the saline-injected control nymphs in the other experiments (∼18 mg). In addition, ethanol appeared to affect the ability of R. maderae nymphs to diet-mix. For example, percentage sucrose intake was significantly less in the ethanol-treated controls (53.8%) compared with nymphs injected with spiperone (68.1%) or, in other words, percentage casein intake was significantly higher in ethanol-injected controls (46.2%) compared with nymphs injected with spiperone (31.9%). The ethanol appeared to cause a reduction in feeding in the control nymphs in this experiment and, based on the percentages listed above, the majority of this reduction is a result of decreased sucrose feeding. Consistent with these results, when honeybees were fed with 10% ethanol, after 24 h, they showed a significant decrease in the amount of sucrose eaten compared with control bees (Mustard et al., 2008). In this experiment, ethanol may be affecting the perceived state of hunger. The DA antagonist spiperone was dissolved in 100% ethanol, and spiperone completely reversed the effect ethanol had on satiety. Interestingly, ethanol consumption in vertebrates has been shown to lead to the release of DA (Tupala and Tiihonen, 2004). Experiments on R. maderae nymphs have confirmed that DA causes a reduction in feeding. If DA is potentially released by the presence of ethanol, it may explain the decrease in sucrose consumption in control nymphs injected with ethanol and the ability of spiperone as a DA antagonist to reverse the anorectic effect of ethanol on R. maderae nymphs.

To rule out the possibility that the low consumption values shown by the control nymphs in the spiperone experiment were not due to motor depression caused by ethanol, a motor activity test was conducted. A previous study has shown that ethanol consumption in insects can have negative effects on locomotion, such as a reduction in walking behavior and the loss of the righting reflex (Maze et al., 2006). Results from this experiment showed that ethanol did not affect locomotion in R. maderae nymphs (Fig. 6). As ethanol hemolymph levels have shown time-dependent changes after ingestion in the honeybee (Mustard et al., 2008), R. maderae nymphs were tested at four time intervals. Results on R. maderae showed that time post-injection had no affect on locomotion (Fig. 6).

These results suggest that because locomotion was not impaired in nymphs injected with ethanol, the low values consumed in the spiperone experiment by nymphs injected with ethanol were probably not due to motor deficits. In summary, the experiments with DA, the DA agonist 6,7-ADTN and the DA antagonist spiperone strongly suggest that the neurotransmitter DA is involved in regulating feeding in the cockroach R. maderae. If DA is in fact controlling feeding behavior in insects, then questions remain as to where the proposed regulation occurs (i.e. CNS, peripheral nervous system or a combination of both). DA is found in high amounts in the insect nervous system. DA receptors have been identified in the brain of the cockroach P. americana (Orr et al., 1987) and also in motorneurons of the prothoracic ganglion of its ventral nerve cord (Davis and Pitman, 1991). DA receptors have also been localized in the brains of many insects. Honeybees (Apis mellifera) expressed DA receptor mRNA in all regions of the brain, including cells scattered around the antennal and optic lobes and in Kenyon cells within the mushroom bodies (Beggs et al., 2005). In Drosophila melanogaster, both larvae and adults showed strong DA receptor expression in the mushroom bodies and ventral nerve cord (thoracic and abdominal ganglia) adults also showed expression in the central complex (the brain structure controlling higher-order motor control in insects), near the outer edge of the optic lobe and near the antennal lobe (Kim et al., 2003 Draper et al., 2007). The wide distribution of DA receptors in the insect CNS suggests that the effect of DA on diet regulation may in fact be acting centrally.

At this point in our laboratory, we have now described many neural signals that appear to regulate feeding behavior in the R. maderae cockroach. These experiments have shown that DA appears to be a signal in terminating the current meal in order to avoid hyperphagia. In contrast, OA appears to be a signal for initiating food intake in order to prevent starvation, as OA and OA agonists caused an increase in both carbohydrate and protein intake (Cohen et al., 2002). 5-HT seems to be essential for macronutrient selection, as experiments with R. maderae nymphs showed that increased levels of 5-HT caused a reduction in carbohydrate feeding only (Cohen, 2001). Thus, DA and OA seem to be more involved in controlling aspects of meal size, while 5-HT seems to be involved in appetite by regulating nutrient type. All of this feeding data provide useful insight into the regulatory pathways (i.e. dopaminergic, octopaminergic, serotonergic) that may control dietary behavior in all insect species. In addition, one key objective of animal research is to generate theories about the mechanisms of human biology. Thus, an ideal model subject should be simple enough to study yet display similarities to the mammalian physiology. Insects possess simpler nervous systems than mammals but display many complex behaviors, allowing them to be useful models to understand the various mechanisms in the mammalian feeding system (Mustard et al., 2005). Knowing that insects may be viable models to study the regulatory pathways that control feeding in mammals, insects can potentially be used to examine the effects of anti-obesity drugs or anti-anorectic drugs, hopefully providing treatment one day for life-threatening conditions, such as obesity and anorexia nervosa.


Biological and Pharmacological Aspects of the NK1-Receptor

The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

1. Tachykinins and Their Receptors

The tachykinins are one of the largest conserved families of peptides involved in neurotransmission and inflammatory processes. The idea that tachykinins act exclusively as neuropeptides is currently being challenged. Substance P (SP), a small undecapeptide present in both mammalian and nonmammalian species, was the first member of the family to be discovered (as early as 1931, by von Euler and Gaddum). SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, cell survival, and metastatic dissemination [1–5]. The three classical members of the mammalian tachykinin family are SP and neurokinin A (NKA), both encoded by the TAC1 gene, and neurokinin B (NKB), encoded by the TAC3 gene. A third mammalian tachykinin gene (TAC4) codes for hemokinins and endokinins [1, 6, 7]. The TAC1 gene (according to the Human Genome Organization (HUGO) Gene Nomenclature Committee (http://www.genenames.org/) also encodes other tachykinins, including NKA, neuropeptide K (NPK). and neuropeptide γ (NPγ). On the other hand, the TAC3 gene only codes for NKB (previously known as PPT-B gene). In 2000, Zhang et al. identified a third gene called TAC4 (previously named preprotachykinin-C (PPT-C)) and demonstrated its association with the hematopoietic system and the maturation of B lymphocytes [7]. This gene encodes hemokinin 1 (HK-1) and its shorter derivative hemokinin (4–11) and four other peptides called endokinins (EKS), EKA, EKB, EKC, and EKD [6].

Tachykinin receptors have been divided into three different types according to their affinity ligands (high or low): TACR1 (NK-1 receptor), TACR2 (NK-2 receptor), and TACR3 (NK-3 receptor) (Table 1), which have preferential (but not exclusive) affinities for SP, NKA, and NKB respectively [8–10]. The order of potency of these receptors per tachykinin is shown as follows [10, 11]. Order of affinity of tachykinin receptor by its agonists is (a) Receptor NK-1: SP>NKA>NKB (b) Receptor NK-2: NKA>NKB>SP (c) Receptor NK-3: NKB>NKA>SP.

NPγ and NPK preferentially bind to the NK-2 receptor. The affinities of NKA and NKB for the NK-1 receptor are, respectively, 100 and 500 times lower than that of SP [12]. It has also been reported that SP interacts with fibronectin (FN) and hematopoietic growth factor inducible neurokinin-1 type (HGFIN) [13, 14]. The homology between the NK1 receptor and HGFIN has recently been described. This finding may be relevant because both the NK-1 receptor and HGFIN have been linked to tumorigenesis, including breast cancer (BC) [14]. However, whereas the NK-1 receptor has been described as a tumor promoter, HGFIN may act as a suppressor [14].

The three tachykinin receptors belong to family 1 (rhodopsin-like) G protein-coupled receptors (GPCRs) and are encoded by five exons [9, 15]. These are seven-transmembrane-helix receptors which share the same structural unit: three extracellular (EL1, EL2, and EL3) and three intracellular loops (C1, C2, and C3) with the possibility of a fourth loop, due to the palmitoylation of cysteine (Cys), flanked by seven intermembrane domains (TM 1-VII), and an amino-terminal extracellular and carboxy-terminal cytoplasmic domain [9] (Figure 1).

The carboxy-terminal conserved domain of tachykinins (Phe-X-Gly-Leu-Met-NH2) interacts with tachykinin receptors, while the amino-terminal sequence is responsible for the specificity of the receptor [16]. All tachykinins are amidated at the C-terminal and deamidation suppresses their activity [8]. The second and third loops are involved in the binding of agonists or antagonists, while the third cytoplasmic loop is responsible for binding to protein G. The C-terminus contains serine/threonine residues which, once phosphorylated, cause desensitization of the receptor when it is repeatedly activated by the agonist. The 5′ region of the gene has several putative regulatory DNA elements such as the cAMP responsive element, AP-1, AP-2, AP4, NF-кB, OCT-2, and a domain Sp-1 [16]. Specifically, the NK-1 receptor has 407 amino acids and a relative molecular mass of 46 kDa [17]. NK-2 and NK-3 consist of 398 and 465 amino acids, respectively, NK-3 being the longest of the three receptors. The most important splicing identified loses the last 96 amino acids at the C-terminus and thus has 311 amino acids [18–20] (Figure 1). This shorter or truncated isoform (NK1-Tr) is generated when the intron located between exons 4 and 5 is not removed and the premature stop codon is identified before starting exon 5.

Lai et al. [21] observed that SP specifically increased intracellular calcium in embryonic kidney cells (HEK293) stably transfected with the long isoform, while there was no effect in those transfected with the truncated isoform. Likewise, cells expressing the long isoform activated NF-B and IL-8, while those expressing the truncated one had a lower mRNA expression of IL-8 and were unable to activate NF-кB. The activation of protein kinase Erk was also altered in the same cells: whereas phosphorylation of this protein through the long isoform was fast (1 to 2 minutes) and sustained, cells transfected with truncated isoform were not able to phosphorylate Erk protein within 20 min after exposure to SP [21]. In addition, other studies have demonstrated that SP had a lower relative affinity for the truncated receptor form (up to 10 times less than the full isoform) [18]. Moreover, the loss of certain C-terminal serine and threonine residues is important for G protein-coupled receptor kinase (GRK) interaction and β-arrestin recruitment for subsequent receptor internalization [22–24].

Therefore, the truncated form should be capable of prolonging the responses after ligand binding because its desensitization and internalization are affected. Besides the differences between the two isoforms, another important phenomenon involved in the receptor signaling should be mentioned. Tansky, Leeman, and Pothoulakis showed that the amino terminal end had two glycosylated Asn (N-) sites and described how these glycosylations can influence the functional level of the receptors [25].

They observed that nonglycosylated receptors showed half the affinity for SP shown by glycosylated receptors, and in fact the nonglycosylated NK-1 receptor was internalized faster than the glycosylated form. This also suggested the possibility that glycosylation may be a feature in the stabilization of the receptor in the plasma membrane. Several bands of different molecular weights have been identified, probably due to this phenomenon. For example, in lymphocytes, certain forms of glycosylated receptor (58 kDa) have been described [26], while others with bands of 38 and 33 kDa appear in IM-9 lymphoblasts (26). Furthermore, isoforms with bands of 75, 58, 46, and 34 kDa have been identified in several studies of tumor pancreatic carcinoma cell lines [27, 28].

In the past two decades, other isoforms have been identified besides the conventional ones, with different SP affinities. For example, in rat salivary glands another apparently truncated isoform has also been detected in the C-terminal end, with 8 kDa less than the long isoform [29]. Li et al. also demonstrated that the short isoform seems to have an SP affinity similar to that of the complete isoform. It has been suggested that this isoform comes from posttranslational modifications [30]. In addition, other studies have shown that some receptor isoforms present different affinities from the “classic” forms. This has led to a division of the NK-1 receptor into three different classes: (1) the “classic” NK-1 receptor (which shows greater binding affinity for the SP ligand), (2) the “sensitive to septide” NK-1 receptor (showing a very similar affinity for binding to SP and other tachykinins as NKA, NPK, NPγ, NKB, and even other synthetic peptides such as septide fragment 6–11 SP, which gives the receptor its name) [10, 31], and (3) the “new NK-1 sensitive” receptor [32]. This subtype has a higher affinity for longer tachykinins and does not bind to septide or SP (6–11). However, more studies are needed to identify the real differences in the signaling pathways of each NK-1R isoform and the preferred sites of expression of the different isoforms or glycosylated forms.

1.1. Signaling Pathways Modulated by Tachykinins and Their NK-1R

The physiological processes mediated by SP or other tachykinins occur via the NK-1 receptor, which belongs to the large family of G-protein-coupled receptors (GPCRs). Via second messengers, G proteins activate transduction pathways within the cell. Which pathways are activated by G proteins depends on the nature of the proteins belonging to this large family: for example, the activation of NF-κB mediated by SP, interleukins, or growth factors (IL-1, IL-6, IL-8, TNF-α, and IFNy) and the activation of MAPKs pathway or PI3K/Akt among others [33–35].

1.1.1. GPCR-Mediated Signal Transduction: Classification and Function of G Proteins

GPCRs mediate their signaling through heterotrimeric G proteins transmitting signals from a variety of surface cell receptors to enzymes and ion channels. This complex is composed by three distinct subunits: the Gα subunit that binds to GDP/GTP and the Gβ and Gγ subunits that form the Gβγ complex (which present strong bindings between them) [36, 37]. After binding SP to the specific NK-1 receptor, a change occurs in the Gα subunit, allowing it to exchange GTP for GDP and permitting the dissociation of the Gβγ dimer. These subunits (Gα and Gβγ) begin their own signaling cascade separately and positively or negatively regulate the activity of enzyme effectors and ion channels that are cell type- or GPCR-specific [38, 39].

The GTP hydrolysis returns the Gα subunit to its inactive state, allowing again the trimeric formation with the Gβγ subunit [40]. Gβγ in contrast to the Gβγ subunit, the broad range of the α subunit is limited because all α subunits, except

, have a palmitic acid posttranslational modification in the amino-terminal portion, which keeps them adhered to the plasma membrane [41]. The α subunit itself has intrinsic GTPase capacity and may modulate its own inactivation. In any case, this GTP hydrolysis is relatively low compared with other accessory proteins called cytoplasmic regulators of G protein signaling (RGS) [42] (Figure 2). (i)

: the receptor interaction by the agonists regulates the activation of protein and the subsequent activation of phospholipase Cβ (PLCβ), which degrades the phosphatidylinositol 4, 5-bisphosphate (PIP2) to produce two compounds: diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), responsible for increasing intracellular calcium [43–47]. (ii)

: this subunit is responsible for the activation of the second messenger adenylate cyclase (AC), which catalyzes the conversion of cytoplasmic ATP into cyclic adenosine monophosphate (cAMP) when the Gs-related pathway is activated (by contrast, AC inhibition is conducted by the Pertussis toxin-sensitive

-protein (PTX) in rat submandibular cells) [48]. Other studies have reported that the Gs subunit is the substrate of cholera toxin (CTX), produced by Vibrio cholerae, which catalyzes its ADP ribosylation and inhibits its intrinsic GTPase activity [42]. It has been widely reported that increased cAMP levels lead to activation of protein kinase A (PKA). Activation of PKA, then, phosphorylates the transcription factor CREB (cAMP-responsive element-binding protein CRE). CREB binds to the cAMP response element (CRE) of a target gene and negatively affects the activation of NF-кB [49]. However, despite the Gs action, the power to generate cAMP accumulation by NK-1R agonists is lower than the ability to induce IP3 and intracellular calcium of [50]. (iii) : the role of this class member is to mediate the inhibition of different types of AC. Functional studies have been conducted with PTX, produced by Bordetella pertussis. Unlike CTX, PTX decouples the G protein from its receptor and remains inactive and bound to GDP [51]. (iv) G12/13: this subunit is expressed ubiquitously in mammals and is composed by two proteins, Gα12 and Gα13 which are also toxin resistant [42]. Meshki et al. reported that the G12/13 subunit could regulate changes in cytoskeletal rearrangement when the cell was preparing to migrate. These changes depend on the activation of Rho/Rock which directly modulates the myosin regulatory light chain. Phosphorylation of this protein is associated with the formation of small spherical outgrowths arising from the membrane known as bubbles or blebs, in a process known as blebbing. This process is not always associated with apoptosis but may be associated with the cytoplasmic disorganization at the time of cell migration and Meshki et al.’s study showed how the NK-1 receptor had the ability to interact with the G12/13 protein throughout this process [52]. (v)

: this subunit is one of the most abundant G proteins in neuronal and neuroendocrine tissues [53]. Nishimura et al. provided the first evidence of NK-1R’s potential to activate in Sf9 cells [54]. This subunit signals downstream of frizzled (Fz) GPCRs. is crucial for the activation of Wnt-β-catenin signaling pathways [42]. While is abundant in nervous tissues, its deficiency causes lesions that appear to be mediated mainly by this subunit [42, 55]. The Gβγ subunit has been less studied than Gα. The βγ complex can be formed by five different β subunits and 12 γ subunits [42]. At first, it was thought that its role was merely passive but later it was found that it may play a role in the activation of effectors such as PLCβ, adenylyl cyclases, PI3K, K + ion channels, and Src. All these associations between trimeric G proteins and second messengers lead to a cascade of intracellular events that cause a particular response, depending on cell type.

GPCRs constitute a large family of cell surface receptors which regulate many cellular functions, including cell proliferation, survival and motility, the sense of smell, emesis, and depression. They have recently emerged as key receptors in tumor growth, angiogenesis, and metastasis.

Specifically, interactions involving the protein occur in several systems and endocrine secretion, vasodilatation, neuromodulation, and activation of monocytes as well as in cell proliferation [56–60]. Therefore, experimental evidence from several recent studies supports the view that alterations in the endocrine system regulated by NK-1R and SP contribute to the development of pathologies such as depression, neural degeneration, alcohol addiction, pain, migraine, inflammatory bowel disease, pruritus, viral infection, bacterial infection, cancer, and emesis [27, 35, 61–65].

1.1.2. Signaling Pathways of NK-1R and SP

The NK-1 receptor signals through different pathways depending on the nature of the G proteins. For example, in glioblastoma cell lines and in many other tumor types, the SP binding causes the accumulation of DAG, which in turn activates PKC. This protein phosphorylates other proteins such as c-Raf-1 and MEK, which phosphorylate tyrosine protein kinase Erk1/Erk2 (also known as p-42/44) of the MAPK protein family [27, 65–69]. The mechanism by which PKC activates ERK is not entirely understood. Discordant results are found in the literature, in which different molecules have been implicated in MAPK activation via GPCRs. These disparities may be explained by differences in the cell culture methods used or the nature of the samples analyzed [70–76]. Subsequently, transcription factors such as c-fos or c-myc are activated and induce DNA synthesis and cell proliferation (Figure 3). Another protein kinase activated by NK-1 receptor is PKCδ. Earlier studies by Della Rocca et al. [77] found that PLC activation dependent on both (α1B adrenergic receptor) and Gβγ subunits (Gi dissociated from α2A adrenergic receptor protein) increased cytoplasmic IP3 levels, resulting in an increase in cytoplasmic Ca 2+ . High concentrations of intracellular calcium, probably through calmodulin, lead to kinase activation, called proline-rich tyrosine kinase 2 (Pyk2, English protein tyrosine kinase 2) associated with focal adhesion kinase (FAK). In turn, this Pyk2 activity (now known as PTK2B) regulates kinase protein Src. Src-dependent tyrosine phosphorylation of adaptor proteins such as Shc recruits Grb2-SOS complex to the plasma membrane and initiates the phosphorylation cascade leading the Erk1/2 activation that triggers cell proliferation pathways [77].

According to some studies, MAPK activation depends not only on G proteins and their canonical or classical pathway signaling, but also on the scaffold for the assembly of multiprotein complexes for NK-1R internalization or other GPCRs. In some models such as Gαq-coupled proteinase-activated receptor 2 (PAR2), the interaction of this receptor with β-arrestin internalization proteins causes a retention of Raf-1 and phosphorylated Erk1/2 proteins in the cytoplasm and these proteins cannot be transferred to the nucleus [78].

However, others such as the β2-adrenergic receptor (β2-AR) are internalized through the complex formed by β-arrestin, Src, and Erk [79]. In this case, β2-AR receptor activation causes Erk1/2 phosphorylation and induces a different set of cellular responses to those produced by PAR2, since Erk1/2 is not retained in the cytoplasm. These differences may be due to the different scaffolding protein complexes responsible for the distinct subcellular localization of activated kinases for internalization, because they may be responsible for governing the mitogenic potential of each particular signal.

The requirement for β-arrestin-dependent endocytosis differs between receptor types. This variation also appears to be cell type-independent, as the two receptors (NK-1R and PAR2) expressed in the same cell line (KNRK) induce the formation of different protein scaffold complexes [22]. Therefore, better studies are needed to identify the GPCR C-terminal end responsible for the internalization process, since this cytoplasmic tail is the key for binding proteins. Feng et al. [23] observed that stimulation of the NK-1 receptor (overexpressed in KNRK cells or naturally expressed in endothelial cells) by SP, activated Erk1/2 via a β-arrestin-dependent mechanism. SP induced the formation of a multiprotein complex near the plasma membrane containing β-arrestins, Src, and Erk1/2. Once activated, Erk1/2 translocates into the nucleus to induce proliferation and antiapoptotic effects [22].

NK-IR internalization and recycling seems to modulate cellular responses to SP binding, and although SP is degraded, the receptor recovery towards the plasma membrane does not seem to be dependent on new protein synthesis [80].

In addition to its mitogenic activity, SP is also capable of stimulating cytokine release from normal cells and immune cells from the tumor microenvironment in order to promote tumor progression. Moreover, the NF-кB-mediated G protein is involved in several cell types. It has been shown that tachykinins activate NF-кB and stimulate the production of proinflammatory cytokines in several cell types: colon epithelial cells [34], macrophages [81], mast cells [82], T cells [83], and astrocytoma cells [84] and in a lung adenocarcinoma epithelial cell (A549) [56]. However, not all the mechanisms by which this activation occurs are totally known. NF-кB activation by SP is calcium-dependent in astrocytoma cells, but not in colon epithelial cells [34, 81].

Another downstream effector of the various signaling pathways activated by NK-1R is the serine/threonine protein kinase Akt, also known as kinase B (PKB) protein. Phosphoinositol 3-kinase or PI3K is responsible for activating Akt. PI3K can be activated by receptor tyrosine kinases (RTKs) or by integrins transactivation or GPCRs [85]. It is unclear how G proteins activate PI3K, but it is known that PIP2 is converted to PIP3 (capable of activating Akt) by PI3K, whereas PTEN opposes this reaction by dephosphorylating PIP3. The role of Gβγ subunit in PI3K activation has also been reported, because it is known that there is a direct activation of kinase by the βγ dimer [85] (Figure 3). González Moles and colleagues [86] reported that stimulation of the bradykinin receptor (a receptor of the same family as NK-1) by Gαq and β1γ2 subunits increased Akt phosphorylation due to PI3K and this was responsible for NF-кB activation in HeLa transfected cells. These results suggested that if bradykinin receptor phosphorylation leads to IKK2 activation, then activation of Gαq, β1γ2, PI3K and Akt is required (Figure 3). However, these authors reported that inhibition of PI3K and Akt only partially inhibited the activation of downstream proteins, so their study does not exclude other parallel signaling pathways such as those mentioned above, including the MAPK pathway.

Finally, other intracellular signaling mechanisms by which NK-1R is responsible for SP-induced cell shape changes have also been described. These changes depend on the activation of Rho/Rock which directly modulates the myosin regulatory light chain. Meshki and collaborators reported that NK1R has the ability to interact with proteins from the G12/13 family [52].

Therefore, all these studies have identified key molecules involved in NK-1R signaling, in various cell types, such as p42/44 protein (MAPK), p38 MAPK, NFкB, PI3K, Akt, Src, EGFR, Rho/Rock, β-arrestin, and Pyk2 depicted in Figure 3.

2. Distribution of Tachykinin Receptors in the Body

As previously mentioned, tachykinins and their receptors are widely expressed in various human systems such as the nervous [19, 87–89], cardiovascular [90–93], genitourinary [94], immune systems, gastrointestinal tract [28, 95–102] and in some tissues such as salivary gland [103], skin, and muscle (Figure 4). Tachykinin receptors are not evenly distributed. The NK-1 and NK-3 receptors are found in the nervous system and in peripheral tissues, whereas the NK-2 receptor is found only in the peripheral tissues (kidney [104], lung, placenta [105] and skeletal muscle) [57, 106, 107]. Specifically, like its higher affinity ligand SP, the NK-1 receptor is involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis but also the sensory neuronal transmission associated with depression, stress, anxiety and emesis. Additionally, the NK-1 receptor is responsible for modulating the immune system’s inflammatory response. Expression of the NK-1 receptor has been identified in lymphocytes, monocytes, macrophages, NK cells and microglia. NK-1R is also expressed in bone marrow cells (cells of lymphoid and myeloid lineage) and is considered an hematopoietic regulator [58, 108–112]. Both in normal tissue and during hematopoiesis, NK-1R mediates stimulation effects and NK-2 exerts suppressor functions (when NK-1R is expressed in normal cells, there is a down-regulation of NK-2R) [113, 114].

3. NK-1R as a Therapeutic Target

SP, through the NK-1 receptor signal, has been implicated in the regulation of many physiological and pathophysiological functions such as neuronal survival, regulation of cell movement, pain, inflammation, salivation, depression, stress responses, emotions, reward, neurogenesis, vigilance, cancer progression, and emesis [63, 115–123]. Moreover, the tachykinergic system can regulate motility in several cells [52], stimulates platelet aggregation [124], and is present in many human body fluids such as breast milk, blood, saliva, and cerebrospinal fluid [122]. The ubiquity of the SP/NK-1 receptor system in many biological functions and its upregulation under pathological conditions makes this system an important target for several diseases (depression, neural degeneration, alcohol addiction, pain, migraine, inflammatory bowel disease, pruritus, viral infection, bacterial infection, cancer, and emesis [27, 35, 61–65]). Among all these conditions, the NK-1R antagonist has only been subject to clinical development in the treatment of chemotherapy-induced nausea and vomiting (CINV) and in depression. These clinical trials led to the registration of aprepitant by the regulatory agencies EMA and FDA as the first NK-1 receptor antagonist to treat chemotherapy-induced nausea and vomiting.

3.1. Emesis

NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and area postrema) [125]. Aprepitant (MK-869, brand name EMEND) is the first the neurokinin-1 receptor antagonist to be commercialized. When added to a standard regimen of a 5-HT3 receptor antagonist and dexamethasone in cancer patients receiving highly emetogenic chemotherapy, aprepitant improves the complete response (CR) rate in acute CINV. It also improves the CR in delayed CINV when used in combination with dexamethasone compared with dexamethasone alone [126]. The use of aprepitant in patients receiving moderately emetogenic chemotherapy was recently approved after phase III clinical trials had demonstrated its efficacy [127]. Aprepitant is a substrate, a moderate inhibitor, and an inducer of cytochrome P450 (CYP3A4) and CYP2C9. Drug interactions should be monitored when aprepitant is given together with agents affected by CYP3A4 and CYP2C9 isoenzymes.

Aprepitant is the only antagonist with high affinity for the NK-1 receptor approved to date by the US Food and Drug Administration (FDA). It was approved in 2003 for oral administration. In 2008, its prodrug, fosaprepitant, was approved for intravenous use.

These two drugs are the only available agents in this class for preventing chemotherapy-induced and postoperative nausea and vomiting. However, other agents such as netupitant and rolapitant are currently undergoing phase III clinical trials and are expected to be commercialized in the near future [128]. More information on NK-1R as a target for CINV will appear in the following pages of this issue.

3.2. Depression

The NK-1R antagonist was tested as a novel antidepressant mechanism in an exploratory phase II clinical trial also using aprepitant [121].

In situations of stress and anxiety, neuropeptides such as SP are released at a rate proportional to the intensity and frequency of stimulation [129]. In fact some studies show that the SP/NK-1R interaction plays an important role in the regulation of emotional behavior [129]. There is evidence that psychosocial help reduces depression, anxiety, and pain and may prolong survival in some cancer patients. Indeed, various forms of stress have been associated with mammary tumorigenesis [130, 131]. Specifically, the NK-1 receptor and SP are involved in emotional responses to stress, suggesting that an alteration in the tachykinergic system may be the key to triggering pathogenesis such as depression (SP expression has been shown to increase during depression [121] whereas the genetic deletion of its receptor induces an anxiolytic and antidepressant effect [132]). It has even been reported that psychotropic drugs modify the expression of genes encoding the synthesis of tachykinin in some areas of the rat brain [133, 134]. Some of these findings suggest that a reduction in SP levels in certain regions of the brain, with NK-1R antagonists, may have a therapeutic effect as antidepressant drug in affective disorders and also in disorders related to cancer. In fact, several publications and reviews have reported experiments correlating emotional behavior (the limbic system) and cancer [35, 135, 136].

3.3. Cancer

Experimental evidence obtained in recent years supports the idea that alterations in the neuroendocrine system may contribute significantly to the tumorigenic process. The tachykinins act directly on tumor cells, modulating their responses in terms of proliferation and survival but also contribute indirectly by altering the tumor microenvironment and processes related to tumor progression. SP and its receptor are expressed in a wide variety of tumor cell lines (WERI-Rb-1 and Y-79 from retinoblastoma, U373 MG and GAMG from glioma, SNK-BE(2), Kelly and IMR-32 from neuroblastoma, CAPAN-1 and PA-TU 8902 from pancreatic cancer, Hep-2 from laryngeal cancer, 23132/87 from gastric cancer, and SW-403 from colon cancer) [65, 67, 137] and tumors such as astrocytomas, gliomas, neuroblastomas, pancreatic cancer, melanomas, and breast cancer [28, 86, 123, 135, 138, 139].

It has been estimated that the NK-1R antagonist aprepitant is 45000 times more selective than for the NK-2 receptor and more than 3000 times more selective for the NK-1 receptor than for the NK-3 receptor [140]. This compound has shown antiproliferative properties in tumoral cell lines of glioma, neuroblastoma, retinoblastoma, pancreas, larynx, colon, and gastric carcinoma [62, 64, 141, 142]. A clinical trial for moderate to severe depression, at a dose of 300 mg/day, found this compound to be safe and well tolerated. No statistically significant differences were found comparing adverse events with patients treated with placebo [121]. Although no clinical trials have yet been initiated, there are sufficient preclinical data to believe that NK-1R antagonists may one day be assessed as anticancer agents [3, 5, 28, 35, 62, 64, 122, 123, 137, 138, 141–148].

4. Conclusion

The NK-1 receptor is the high affinity receptor of SP, the major mammalial tachykinin. It belongs to the G protein-coupled receptors (GPCRs) family. Tachykinins and their receptors are widely expressed in various human systems. NK-1 receptors are found in the nervous system and in peripheral tissues. Specifically, the NK-1 receptor is involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. Also it acts as a neuromodulator contributing to brain homeostasis and sensory neuronal transmission associated with depression, stress, anxiety, and emesis.

NK-1R and SP are present in brain regions involved in the vomiting reflex (nucleus tractus solitarius and in the area postrema). This anatomical localization has led to the successful clinical development of antagonist against NK-1R in the treatment of CINV. Aprepitant is the first NK1R antagonist of this new antiemetic family. Two other NK-1R antagonists have finished clinical trials and it is expected that they will be commercialized in the near future.

Conflict of Interests

The authors have no potential conflict of interests to declare.

Acknowledgments

This work has been partially funded by a grant from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (PI12/01706), by a grant from the Fundación Cellex and by Redes Temáticas de Investigación en Cáncer (RTICC, RD12/0036/0055) (http://www.rticc.org/). This study was supported by grants from the Fondo de Investigación Sanitaria (PI08022), Instituto de Salud Carlos III-Subdireción General de Evaluación y Fomento de Investigación, Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa, the Fundación Cellex, and Redes Temáticas de Investigación en Cáncer (RTICC, RD07/0020/2014).

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Copyright

Copyright © 2015 Susana Garcia-Recio and Pedro Gascón. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


How are neuromodulator receptors distributed? - Biology

Trace amines (TA) are endogenously produced in mammals, have a low concentration in the central nervous system (CNS), but trigger a variety of neurological effects and intervene in host cell communication. It emerged that neurotransmitters and TA are produced also by the microbiota. As it has been shown that TA contribute to wound healing, we examined the skin microbiome of probands using shotgun metagenomics. The phyla Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes were predominant. Since SadA is a highly promiscuous TA-producing decarboxylase in Firmicutes, the skin microbiome was specifically examined for the presence of sadA-homologous genes. By mapping the reads of certain genes, we found that, although there were less reads mapping to sadA than to ubiquitous housekeeping genes (arcC and mutS), normalized reads counts were still >1000 times higher than those of rare control genes (icaA, icaB, and epiA). At protein sequence level SadA homologs were found in at least 7 phyla: Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, Acidobacteria, Chloroflexi, and Cyanobacteria, and in 23 genera of the phylum Firmicutes. A high proportion of the genera that have a SadA homolog belong to the classical skin and intestinal microbiota. The distribution of sadA in so many different phyla illustrates the importance of horizontal gene transfer (HGT). We show that the sadA gene is widely distributed in the human skin microbiome. When comparing the sadA read counts in the probands, there was no correlation between age and gender, but an enormous difference in the sadA read counts in the microbiome of the individuals. Since sadA is involved in TA synthesis, it is likely that the TA content of the skin is correlated with the amount of TA producing bacteria in the microbiome. In this way, the microbiome-generated TA could influence signal transmission in the epithelial and nervous system.

Keywords: metagenomic profiling microbiome microbiota skin trace amines.

Copyright © 2020 Luqman, Zabel, Rahmdel, Merz, Gruenheit, Harter, Nieselt and Götz.


Types of Receptors

There are literally thousands of different types of receptors in the mammalian body. While there are far too many to start listing out, receptors do fall into some very broad categories of function. Many are used in “cellular signaling”, which is an enormously complex system of signals and responses mediated almost entirely by receptors and the ligands they receive. These include receptor proteins embedded in the cellular membrane which activate other sequences upon receiving a ligand, and the receptors found in the immune system which are structured to find intruding proteins and molecules. Below is the general model for cell signaling, which can take many different forms.

Still other receptors have a high affinity for their ligand, and are used in functions such as binding the cell to the extracellular membrane and other cells. These receptor proteins still change shape when their ligand is bound, signaling to the cell that it is in contact with other cells. Different organisms use this in different ways. Multi-cellular animals use this to orient their cells and ensure the connections between them. Single-celled organisms may use these receptors to signal a defense mechanism or other action when space becomes too crowded. Many receptor proteins are ubiquitous among animals, as they have been conserved throughout evolution due to their extreme usefulness.


Neuronal distribution of tyramine and the tyramine receptor AmTAR1 in the honeybee brain

Tyramine is an important neurotransmitter, neuromodulator, and neurohormone in insects. In honeybees, it is assumed to have functions in modulating sensory responsiveness and controlling motor behavior. Tyramine can bind to two characterized receptors in honeybees, both of which are coupled to intracellular cAMP pathways. How tyramine acts on neuronal, cellular and circuit levels is unclear. We investigated the spatial brain expression of the tyramine receptor AmTAR1 using a specific antibody. This antibody detects a membrane protein of the expected molecular weight in western blot analysis. In honeybee brains, it labels different structures which process sensory information. Labeling along the antennal nerve, in projections of the dorsal lobe and in the gnathal ganglion suggest that tyramine receptors are involved in modulating gustatory and tactile perception. Furthermore, the ellipsoid body of the central complex and giant synapses in the lateral complex show AmTAR1-like immunoreactivity (AmTAR1-IR), suggesting a role of this receptor in modulating sky-compass information and/or higher sensor-motor control. Additionally, intense signals derive from the mushroom bodies, higher-order integration centers for olfactory, visual, gustatory and tactile information. To investigate whether AmTAR1-expressing brain structures are in vicinity to tyramine releasing sites, a specific tyramine antibody was applied. Tyramine-like labeling was observed in AmTAR1-IR positive structures, although it was sometimes weak and we did not always find a direct match of ligand and receptor. Moreover, tyramine-like immunoreactivity was also found in brain regions without AmTAR1-IR (optic lobes, antennal lobes), indicating that other tyramine-specific receptors may be expressed there.

Keywords: G-protein coupled receptor antibody biogenic amines honeybee tyramine.


Consciousness

Evolution of species and general brain organisation and gene selection.

Reinforcement learning AI reward based, curiosity reward based reinforcement. As naked ape consciousness is a product of a biological holarchy of consciousness so any conscious AI will be a product of a technological holarchy of consciousness. In the naked ape the biological holarchy of consciousness is also the holarchy conscience and the holarchy of empathy. A robotic or AI technological holarchy of consciousness must also be a holarchy of conscience and holarchy of empathy for the naked ape.

Universal grammar UG, structural dependence, simple computation merge, the underlying neurological processes that produce language are not available to consciousness, so much of language is not conscious but the underlying neural physiology, emerging out of physiology things thoughts of which we become aware, sometimes not intelligibly with incongruence and unresolved feelings due to cognitive dissonance, coherence emerges congruence (steady state, homeostasis) from temporary resolution of dissonance, neural rewiring - microtuble state reseting? - grey matter and local congruence, global congruence axons dendrites white matter in central nervous system and peripheral nervous systems, system of systems homeodynamics, cerebral autoregulation, blood ph, neuroendocrine HPG HPA HPT, neurotransmission excitation inhibition, emergent thought language consciousness, why philosophy of X is addictive in dissonance resolution dopamine reward,

backward and forward phenomenology of heard speech, sense making of speech requires backward contextualization of perceived sound parts into a coherent whole segment as a structurally dependent (Chomsky) compositional unit , where a whole segment is itself a part of a larger semantic whole, where a coherent whole segment compositional unit is the smallest consciously intelligible part, see Ludwig Wittgenstein Tractatus Logico-Philosophicus for an abstract treatment, the earlier words of a compositional unit cannot be heard until the later words are heard, capabilities in cognition determine experience (Kant), experience of reality is mediate through the ways of acquisition of knowledge, that is of cognition, the biological information value chain of the holarchy of consciousness, the biological consciousness value chain of the holarchy of consciousness, as before knowledge (information) is language (Wittgenstein) so before consciousness is language, intermediating between consciousness and language then epigenetic modes of cognition phenotype potential in addition to innate knowledge acquisition modes of cognition, epigenetic environmental positive feedback loops in phenotype evolution advantage and gene selection, moral dimension of empathy in reinforcing feedback loop gene selection for delayed epigenetic realization of modes of cognition phenotype potential through childhood, as before knowledge is language so phenotype epistemic potential and phenotype language potential parallel expressions of the same underlying multivariate genetic capability, slow evolutionary quantitative cognitive capacity leading sudden qualitative difference at a language knowledge nexus consciousness singularity, cognitive language knowledge nexus a product of connectome complexity - global cognitive space (Changeux) - the realization of a holarchy of consciousness,

Brain plasticity, serotonin 2A, psychoactive substances (lycergic acid, psilocin, mescalin, DMT, . ), psychoactive alkoloids psychedelics like lycergic acid have a very similar molecular structure to serotonin, similarity of psychedelics to serotonin cause it to hijack serotonin receptors,

Classifications of neuroactive chemicals, neurotransmitters neuromodulators neurohormones, are overloaded. Some neuroactive chemicals (peptides) can act in multiple ways depending on where they are synthesized and how deployed. So a neuroactive chemical may be autocrine that is acting on the same cell or paracine that is acting on nearby cells. Longer lasting or

Holarchy of Consciousness

Other brains (epistemic parallelism, group reward, ) Epigenetics, society, communication, cooperation, and self consciousness. , Politics, economics, artifice, war, , . Thermodynamics

Brain, body and mind (epistemic survival, curiosity reward, environment, ecosystem, . ) consciousness and self. language, art, artifacts, psychology., Thermodynamics

Brain (), chemical machine and environmental factors, Phenotype biology, Thermodynamics, Electrochemisitry, Genetic chemistry, Quantum biology, Quantum chemistry, Quantum physics.

Neural assemblies () throughput, information processing, parallelism. Electrochemisitry

Neural layers () throughput, information transmission and transformation, parallelism. Electrochemisitry

Neural networks (connectome, nervous system, senses, ) input, output, information sharing, parallelism. Electrochemisitry

Neural circuits (reflex arcs, local circuits, . ) Electrochemisitry

Neural cells (microtubles) cell information storage function. Quantum biology?

Neural cells () cell information processing function. Electrochemistry

Neural cells () cell life function. Thermodynamics

Neural cells () cell capability function. Genetic chemistry

Biomolecules (neurotransmitters, microtubles, neuropeptides, receptors, enzymes, ionic channels, . ) pharmacology, nee bio-molecular , Quantum biology

Ionization () Quantum chemistry nee molecular quantum mechanics

Atoms (Carbon C, Hydrogen H, Oxygen O, Nitrogen N, Phosphorous P, Calcium Ca, Potassium K, Chloride Cl, Sodium Na, . ) nee human chemical elements. Quantum chemistry, Physical chemistry

Atomic Physics, electron quantized energy levels, no two can have the same , Quantum physics

Thought Leaders

Organizations

Human Genome Nomenclature Committee HGNC, WS

Human Microbiome Project (HMP) Consortium, WS

DeepLabCut, animal pose estimation, GH , WS

Quantum Aspects of Life, 2008, Derek Abbott (Editor), Paul Davies (Editor), Arun Pati (Editor), Roger Penrose (Forward), WP


Watch the video: Chemical Synapses and Neuromodulation (October 2022).