Neurotransmitters and Neuropeptides of Invertebrates
Abstract and Keywords
This chapter introduces working definitions of neuropeptides and neurotransmitters from the perspective of invertebrate physiological processes. Neuropeptides and neurotransmitters are intercellular chemical signaling agents used by all animals. Chemical signaling augments or substitutes for electrical communication in the nervous system. When these agents act as neurotransmitters, they convert electrical signals to chemical signals across the synapse. As hormones, they circulate from a site of release to act at a more distant site in the body of the organism. Neuropeptides and neurotransmitters are classified into these groups mostly on the basis of their molecular size. This article describes several neuropeptide superfamilies and their wide scope of actions in model invertebrates. The article also describes the main neurotransmitters used by invertebrates.
Neurotransmitters and neuropeptides are two classes of molecules that animals with any form of a nervous systems use to send intercellular messages between parts of the nervous system and throughout the body. Chemical substances that communicate signals in the nervous system act either as hormones or neurotransmitters, or both. Hormones enter the circulation from a bona fide endocrine gland or other site to act on the nervous system at a distance from the place they were synthesized. Neurotransmitters fulfill roles in electrochemical communication by local release into the synaptic cleft from vesicles that contain the neurotransmitter in the presynaptic element of the synapse. Signaling molecules often act as both hormones and neurotransmitters, for example, vasopressin and serotonin.
Dale’s principle, formulated by Eccles (1957, 1964) in the late 1950s, stated the idea “one nerve utilises one transmitter” (Burnstock, 2014, p. 1). In the decades since, important discoveries have repeatedly refuted the idea embodied in Dale’s principle. It has been demonstrated that a single neurotransmitter, say L-Glutamate (L-Glu), can operate both in the central and peripheral nervous systems. It has been shown that more than one neurotransmitter and/or neuropeptide can be contained inside a synaptic vesicle for release into the synaptic cleft and act on the postsynaptic cell. The multiple signaling agents will act synergistically or antagonistically over morphological or temporal scales to increase the available repertoire of a nerve granted by its excitatory potential.
This chapter takes up the subject of invertebrate neurotransmitters and neuropeptides from a physiological perspective. It treats together a signaling agent’s actions as a hormone and as a neurotransmitter. This approach was adopted because there is less argument about designations as neurotransmitter or neuropeptide than there is about hormone versus neurotransmitter. Short-acting chemical agents that modulate intercellularly, rather than carrying the message synaptically between excitable cells, could be classified as hormones, neuromodulators, or paracrine agents. An example is ATP co-released with another neurotransmitter from synaptic vesicles that act on a glial membrane near the synapse (MacDermott et al., 1999). Since activation of tailored receptors in all these membranes often defines the effect observed, it is more important for our purposes to focus on the end effect.
Peptide hormones and neurotransmitters are believed to be the most ancient signaling molecules (Grimmelikhuijzen et al., 2002), and they are not limited to neuronal signaling, although neurons usually serve as either releasers or targets. Most active peptide neurotransmitters are 4–20 amino acids in length, derived from larger precursor hormones that are posttranslationally modified to form often multiple copies of a neuropeptide and more than a single active compound. This may provide redundancies, different potencies at receptors that bind them, or agents with different signaling emphases. Peptides circulate as neurohormones, are synaptically released as neurotransmitters, or both. Simultaneous functions as both hormone and neurotransmitter are the most common. Their diversity of actions allows multifunctionality of the same neural machinery, and it also attests to their longevity. Neuropeptides are broken down and their action terminated by peptidases at the extracellular membrane of the target.
Peptide receptors usually couple to G-proteins (Jekely, 2013). Known invertebrate peptide receptors activate the same second messenger machinery as in vertebrates (Sossin & Abrams, 2009). These authors point out that intracellular signal transduction pathways were in place very early in evolution. Nevertheless, identification of dedicated receptors in invertebrates as a whole lags somewhat behind their identification in vertebrates (Cardoso & Larhammar, 2014), in part because the physiological studies sometimes have not been done. Neuropeptide signaling controls metabolic states such as somatic growth and condition as well as reproductive status, water, and salt balance. Peptide signaling molecules also mediate integration of the sensory environment into the homeostatic conditions of the animal, as in the establishment of clock rhythms.
The role of peptides in mediating invertebrate physiological processes has been studied since the early part of the last century, with the most complete and detailed information emerging from arthropod insect models. Studying the physiological actions of invertebrate peptides in noninsect models has been spotty and largely limited to crustaceans and mollusks. Bioinformatics processing of high throughput sequencing data is beginning to identify peptides plus their receptors in invertebrate phyla based on percent identity to known arthropod proteins. The establishment of physiological roles beyond insects is beginning in these phyla, and these efforts will more fully describe their actions throughout the Metazoa.
The annual special paper collection Invertebrate Neuropeptides (I through XV) published in the journal Peptides since 2001 and edited by Ronald J. Nachman as an outcome of the annual International Invertebrate Neuropeptide Conference is the seminal source of recent collected research on this topic, and the reader is referred there (http://www.journals.elsevier.com/peptides/special-issues) for the latest as well as the classical on the reader’s invertebrate species of choice.
Grouping neuropeptides into families based on structure-function is both a rational impulse and critical to understanding their effects at defined or putative receptors. Considerable super- and subcategorical complexity arises due to prohormone processing into numerous related peptides with sometimes contrasting function. In a pattern found repeatedly in the neuropeptides families, some members have inhibitory effects on metabolic pathways that other members stimulate. This often involves pleiotropy, in which the products of a single gene have unrelated phenotypic characteristics, although superfamilies commonly include numerous genes. Furthermore, the number of repeats change or the sequences diverge into distinct peptides over time (Webster, et al. 2012). Variable naming styles across the invertebrates further complicates the cataloging chore. It is pertinent that peptide names sometimes imply a narrow functional role. Although their actions can be specific, peptides are often named for the first physiological effect noted. Once, and if, wider functions are discovered for the peptide, the name, now an artifact of the originally studied function, can be misleading. These names persist, perhaps because the iconic physiology that defined them was executed so long ago (>100 years in some cases). Another complication is the designation as peptide hormone versus neurotransmitter. The scope of influence of these messengers across the brain and body is not sufficiently straightforward that this is always a clear distinction for a specific peptide. Thus, it can be up to the author to decide, as I have done occasionally here.
Jékely (2013) and Bauknecht and Jékely (2015) recently addressed some gaps and confusion among the categories of invertebrate neuropeptides and their receptors. Their work bridged the organizational distance between better-studied insects and other invertebrates, and due to the emphasis on noninsect invertebrate models here, it served as the categorical treatment of neuropeptides presented. Table S6 from their 2015 work is reprinted here as Figure 1.
Even with categorization, neuropeptides have diverse impacts on biological systems and occasionally appear highly tailored to species, even when their physiological role as a member of a peptide family is conserved. An example is a phosphorylated adipokinetic hormone (AKH) in the beetle Trichostetha fascicularis, whose role is to regulate carbohydrate supply during flight, in this species alone (for now; Gäde et al., 2006). The better we are at identifying neuropeptides and the genes from which they originate, however, the smaller the set of species-specific peptides becomes. Nevertheless, comprehensive summaries of their actions are a daunting task. Neuropeptide complexity and impact are illustrated, however, from consideration of several examples. The first two are examples of central nervous system peptide hormone command function in invertebrates-only neuropeptide groups, the crustacean hyperglycemic hormone (CHH) superfamily and the FMRFamides, while the others are important peptide families across Metazoa.
The arthropod eyestalk X organ-sinus gland is part of the protocerebrum and a source of potent peptide hormones of the crustacean hyperglycemic hormone superfamily (CHH; eighth group from the top on the right side of Fig. 1). This neurohumeral analog of the vertebrate hypothalamus-pituitary system illustrates how centrally released peptides execute command functions, while related compounds as differently spliced proteins or from similar genes have narrower roles. The 80 or so neuropeptide products of approximately 25 CHH genes released from the eyestalk X organ-sinus gland are subgrouped into CHH type I, “true” CHH and ion transport proteins (ITP; Christie et al., 2010) and CHH type II, which are molt-inhibiting (MIH) and gonad-inhibiting hormones (GIH also referred to vitellogenin-inhibiting VIH), but also includes mandibular organ-inhibiting hormone (MOIH), which inhibits secretion of methyl farnesoate from the mandibular organs (Cary et al., 2011; Webster et al., 2012). The CHH peptides are uncommonly large, with type I neuropeptides consisting of 72 amino acids, while type II are even larger at, usually, 78 amino acids. All have structural features in common, especially the three disulphide bonds formed by the characteristic position of six cysteines.
The CHH peptides’ signature role is to regulate carbohydrate metabolism, that is, glycogen mobilization (Christie et al., 2010; Webster, 2012), responding rapidly at times of stress such as during toxicant exposure. Paradoxically, none of the known actions of type II CHH are hyperglycaemic. The effects of the first identified CHH member were of MIH, discovered >100 years ago when Zeleny (1905) noted that eyestalk removal precipitated molting.
An example of how the CHH family resources are marshaled in the bodies of arthropods is provided by insect and crustacean life histories surrounding the periodic molt, or ecdysis. MIH from the X organ-sinus gland inhibits transition to preecdysis by preempting molting hormone (MH) release from the eyestalk Y organ. Release of MH precipitates molting, and once MH is released, the Y organ is refractory to MIH (Chung & Webster, 2003; Nakatsuji & Sonobe, 2004; Nakatsuji et al., 2006). Thus, MIH has master control of elements of the intermolt period up to premolt (Passano, 1953). Critically, CHH is molt-inhibiting in penaeids, lobsters, and crayfish (Chang et al., 1990), but it appears that in crustaceans that preferentially use MIH for this role, CHH also inhibits the molt, with much lower potency (Wainwright et al., 1996).
The main function of CHH in exercise or stress is to mobilize glycogen by increasing glycogen synthase activity, resulting in hyperglycemia in hepatopancreas and muscles. CHH has other nutrient-marshaling actions in that it also stimulates the release of amylase from the midgut gland (Sedlmeier, 1988) and raises titers of phospholipids and free fatty acids (Santos et al., 1997). CHH release and hyperglycemia normally is episodic on a time scale of minutes, with glucose inhibiting the release of CHH in a negative feedback process (Santos & Keller, 1993; Glowik et al., 1997). This energetic function for CHH is not specifically tied to either intermolt or molting, although the molt is a life-threatening stress in the life of arthropods that calls upon glycogen stores (Gäde, 2009). CHH released from the gut, however, causes water absorption to the gut critical to ecdysis (Chung et al., 1999); this is also the role of the CHH family member ITP in insects of xeric environments (Audsley et al., 1992). Last, in pleiotropy of water absorption, a CHH isoform can increase the osmotic concentration of hemolymph, for example, during hyposalinity exposures (Dircksen et al., 2001).
MIOH inhibits the release of methyl farnesoate from the mandibular organs. Methyl farnesoate is a form of juvenile hormone in both insects and some crustaceans (Wainwright et al., 1996; Nagaraju, 2007). Thus, its inhibition precipitates reproductive maturity, for example, oocyte maturation (Jo et al., 1999).
The FMRFamide family of neuropeptides (top left family in Fig. 1) containing Arg-Phe-NH2 at the carboxyl terminus is the product of a single gene (Nässel, 1996). The FMRFamides’ generalized role in invertebrates is control of synaptic transmission at neuromuscular junctions, and muscle contractions (Milakovic et al., 2014). The different mRNA transcripts produced from the FMRFamide gene contain sequences for tetra-, hepta-, and hexapeptides. Expression of one of the different family members is often prioritized in different neurons, and innervation by multiple neurons exerts pleiotropic effects on the same muscle (Van Golen et al., 1995). In other neurons more than one of these peptides occurs. The FMRFamide neuropeptides are used centrally and in motor neurons that control heartbeat, respiration, egg laying, and copulation (Santama et al., 1995; Van Golen et al., 1995).
The GnRH superfamily (tenth family from top left of Fig. 1) is named for the approximately 30-member gonadotropin-releasing hormones of vertebrates (GnRH-I, and –II, also –III in teleosts; Kah et al., 2007; Tsai & Zhang, 2008), whose activation of the hypothalamo-pituitary-gonadal axis initiates reproductive behavior and supresses feeding (Temple et al., 2003; Kauffman & Rissman, 2004; Matsuda et al., 2008).
GnRH induces gonadal steriodogenesis and gametogenesis in vertebrates via its stimulation of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH is also prominent in invertebrates, where it has many actions supporting reproduction, as well as other effects. GnRH is 10–12 amino acids in all animals (Guan et al., 2014). Invertebrate GnRH family members have two additional N-terminal residues compared to vertebrates, but they lack others at the C-terminus (Tsai, 2006). Useful amino acid alignments of both vertebrate and invertebrate GnRH were given by Lindemans et al. (2011).
The GnRH family also is strongly represented in invertebrates by the AKH known from insects, cladocerans such as Daphnia, marine crustaceans like H. americanus and Cancer borealis, and the opisthobranch A. californica, amid perhaps other mollusks for which sequence information was collected (Iwakoshi-Ukena et al., 2004; Roch et al., 2011; Johnson et al., 2014). Red pigment-concentrating hormones (RPCH) and corazonin (CRZ) round out the invertebrate representatives in the GnRH superfamily.
GnRH has broad and pleiotropic actions in invertebrates in promoting/inhibiting reproduction and in contracting/relaxing skeletal and smooth muscle. GnRH is expressed widely throughout invertebrate nervous systems. Octopus vulgaris GnRH (oct-GnRH) increased steroidogenesis in gonads and induced oviduct contraction in addition to stimulating cardiac output (Iwakoshi-Ukena et al., 2004; Kanda et al., 2006). In A. californica, Ap-GnRH is expressed most highly in pedal ganglia, whose motor neurons control the muscles of the parapodia. GnRH caused parapodial relaxation (Johnson et al., 2014). Ap-GnRH also inhibited feeding and promoted attachment to the substrate (Tsai et al., 2010; Johnson et al., 2014); both behaviors precede egg-laying (Macginitie, 1934; Strumwasser et al., 1969; Pennings, 1991). Ap-GnRH inhibited and reversed gonadal maturation and promoted elimination by promoting intestinal contractions. Both actions were shared with AKH in this species (Johnson et al., 2014). In Ciona intestinalis GnRH modulated the gonadal release and synthesis of testosterone and progesterone (D’Aniello et al., 2003).
AKH and RPCH of invertebrates have similar structure. AKH synthesis, release, binding, and actions are fully described (Gäde, 2009; Johnson et al., 2014). The decapeptide AKH is important to carbohydrate and lipid energy mobilization in insects (Bednářová et al., 2013), especially such as during flight (Gäde, 2009). AKH released from the corpora cardiaca gland in the insect brain activates a stimulatory G(q) protein linked to a triacylglycerol lipase or a glycogen phosphorylase in the fat body, where carbohydrates are stored. The lipids are broken down to monoacylglycerols and released into the hemolymph. RPCH control and modulate gut motility via effects in the stomatogastric ganglion (Nusbaum & Marder, 1988; Dickinson et al., 1993, 1997; Johnson et al., 2014), as well as controlling red pigment in the eye (see later; Ranga Rao & Riehm, 1988). CRZ, named for its original purpose in elevating heart rate (Veenstra, 1989), may have actions related to energy budgeting in response to inadequate nutrition (Veenstra, 2009); it has been demonstrated to control insect body color, and it influences the proportional growth of different body segments (Sugahara et al., 2016; Tanaka et al., 2016).
The photonic energy reaching the rhabdomes of each ommatidium of compound eyes of arthropods can be controlled by the fore and aft movement of pigment granules that allow various amounts of light into the ommatidia and control the spectral sensitivity (Autrum, 1981; Ranga Rao & Riehm, 1988; Meyer-Rochow, 2001; Meelkop et al., 2011). The light-adapted scenario has pigments dispersed and thus kept from reaching the rhabdomes, or they can be aggregated in dark-adapted eyes. Pigment movement is controlled by pigment-dispersing and pigment-concentrating hormones, among which are RPCH. The pigment movement hormones, in turn, are released by neurotransmitters. For example, in Uca pugilator, norepinephrine (NE) elicited a light-adapting response, while dopamine (DA) caused a dark-adapting response (Kulkarni & Fingerman, 1986).
Vasopressin and oxytocin (VP and OT; eighth family from top left of Fig. 1) belong to a large superfamily 650 million years old, with strong evolutionarily conservation (Donaldson & Young, 2008; Goodson, 2008). A common ancestral gene in vertebrates underwent duplication in a jawed ancestor (Goodson, 2008) so that these peptides are the products of different genes. Invertebrates, with cephalopods as an exception, have a single gene family homolog (Donaldson & Young, 2008).
The VP superfamily plays two important physiological roles in vertebrates, regulating the hypothalamic-pituitary-adrenal axis, especially related to osmoregulatory and diuretic control at the kidneys, and protecting cerebral blood flow (McEwen, 2004). VP and OT regulate vascular blood pressure via controlling the release of nitric oxide (Katusić, 1992), among other actions, dilating some vessels and constricting others. VP and OT are also social hormones in vertebrates, promoting maternal closeness, are important in social recognition, and mitigate stress (Donaldson & Young, 2008; Wójciak et al., 2012). The structure is a nonapeptide, a covalent ring structure closed by a disulfide bridge, with a flexible tail of three residues, with VT and OT differing by just two residues.
The VP superfamily has been understudied in invertebrates. The osmoregulatory and fluid balance role of VP is conserved in phyla from nematodes to tunicates (van Kesteren et al., 1995; Satake et al., 1999; Kawada et al., 2004; Ukena et al., 2008; Minakata, 2010; Sakamoto et al., 2015). Gruber (2014) summarized functional studies in insects, annelids, gastropods, cephalopods, and C. elegans. Of special note among the roles of VP superfamily members apart from the diuretic and antidiuretic effects is a role in learning in Sepia officinalis and C. elegans (Bardou et al., 2010; Beets et al., 2012; Garrison et al., 2012); a role in reflex behaviors in A. californica (Martínez-Padrón et al., 1992); and a reproductive role in earthworm and the gastropod Lymnaea stagnalis (van Kesteren et al., 1995; Ukena et al., 1995; Oumi et al., 1996; Fujino et al., 1999).
Other important neuropeptide families in invertebrates that have vertebrate counterparts are the growth inhibitory and cardiac activity-modulating somatostatin/allostatins (AST), the allatotropins (AT), which largely oppose the effects of AST on growth, and gastrin/cholecystokinin (CCK)/sulfakinin (SK), whose main roles are associated with inhibition of feeding.
To be defined as a neurotransmitter, a chemical substance must fulfill all of the following critical criteria. It must be present within the synapse, with the machinery for both its synthesis and breakdown also present there, and it must bind and have an action in the synapse (Purves et al., 2001). Refinements of these categories have arisen to require that the substance be released by nerve stimulation, its application to the synapse must mimic the postsynaptic effects of presynaptic stimulation, and its actions must be prevented by an established receptor blocker. By these criteria, L-Glutamate (L-Glu), the major excitatory neurotransmitter in the brains of all metazoans, could not be defined as a neurotransmitter at ionotropic glutamate receptors (iGluR) until the early 1980s (Lee Johnson, 1978; Davies & Watkins 1982a,b; Watkins 1981a,b; Watkins & Evans, 1981; Mayer & Westbrook, 1987). This failure was based primarily on the paucity of specific blockers of the iGluR that could help identify the iGluR subtypes whose actions upon agonist binding were often not uniform. Without the ability to block specific actions of L-Glu at what became known as the subfamilies of N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA- and quisqualate-activated, and kainite) receptors, it could not be unequivocally demonstrated that effects were induced by L-Glu.
One basis for separating neurotransmitters from neuropeptides in classifying communication styles in the nervous system is by size. Neurotransmitters are smaller than neuropeptides, and they are sometimes single amino acids, such as L-Glu, NMDA, and gamma amino butyric acid (GABA). Other small molecule neurotransmitters are NE (also called noradrenaline), epinephrine (EPI), serotonin (5-HT), histamine (HA), and acetylcholine (ACh). One rule of thumb is that if the signaling molecule is larger than three amino acids, it is a neuropeptide (Purves et al., 2001).
We have already described some neuropeptide families that are either demonstrated or putative neurotransmitters used by invertebrates. Invertebrate phyla also use nonpeptide neurotransmitters at receptors that high throughput sequencing techniques are demonstrating are often quite similar to those used by vertebrates. Important in invertebrates are amino acid neurotransmitters L- and D-Glu, D- and L-aspartate (Asp), GABA, glycine, and D-serine. Amine neurotransmitters of invertebrates are HA; the catecholamines DA, NE, and EPI; 5-HT; melatonin; octopamine (OA); and tyramine. A gaseous neurotransmitter is nitric acid (NO). ACh is a small, unique molecule that has perhaps the longest reputation as a defined neurotransmitter, thanks to the frog neuromuscular junction. Most invertebrate model species have all of these as well as a full complement of neuropeptides.
There is one enormous exception, and that is the Phylum Ctenophora. Ctenophores have been proposed as the sister group to all other metazoan animals, based on profound differences in their nervous system for which there is no role for most small molecule neurotransmitters, except L-Glu acting at as many as eight candidate iGluR (Ryan et al., 2013; Moroz & Kohn, 2015, 2016). Aside from L-Glu, none of the critical criteria for traditional neurotransmitters can be filled for ctenophores, although this presumption is based largely on consideration of the genome, in addition to some targeted physiological studies (Moroz & Kohn, 2015), rather than on the basis of extensive physiological studies using all conceivable agonists. Ctenophores express >100 peptide-receptor-like G proteins plus other peptide-receptor like proteins, however, suggesting that neuropeptide signaling may be quite diverse and may convey fast excitatory neurotransmission in the ctenophores (Moroz et al., 2014).
The slightly different architecture of the invertebrate synapse from vertebrates can make it tricky to study the effects of neurotransmitters. When the synapse occurs in the neuropil connecting ganglia, and not near the cell body, the synapse cannot easily be studied by isolating the pre- or postsynaptic neuronal cells (Brown & Piscopo, 2013). When it is not possible to study a synapse electrophysiologically, the chemical presence of either a neurotransmitter or part of its machinery for synthesis or breakdown can be used to indicate the neurochemical nature of the synapse. Thus, although famous invertebrate models tend to be the species in which detailed information is available on the physiological actions of neurotransmitters, stereotyping of neurotransmitter actions can be extrapolated to understudied invertebrate phyla based on these chemical signatures.
ACh mediates fast excitatory cholinergic neurotransmission in the nervous system of all metazoans that use this neurotransmitter. These actions are conveyed via ACh-induced activation of pentameric nicotinic receptors, which are archtypical members of the ligand-activated receptor superfamily that includes 5-HT-, GABA-, and glycine receptors (Sattelle et al., 2005). ACh is synthesized in nerve terminals from acetyl coenzyme A and choline, by the enzyme choline acetyltransferase (CAT), and broken down by acetylcholine esterase (AChE) after reuptake into neurons and glial cells (Banks et al., 2009) by transporters.
Neuromuscular transmission in invertebrates is both glutamatergic (Hooper et al., 1986; Stein et al., 2006) and cholinergic (Futamachi, 1972; Marder, 1974, 1976; Weiss et al., 1992; Brezina et al., 1995; Katz & Frost, 1996; Kratsios et al., 2012), a trait shared with vertebrates (Vyas & Bradford, 1987; Brunelli et al., 2005; Pizzi et al., 2006; Rinholm et al., 2007). Visceral motor activity in crustaceans is commanded by the stomatogastric ganglion and thus is largely cholinergic (Gallus et al., 2006). Independent confirmation of the cholinergic control of gut motility has been found in mollusks and annelids, although numerous other neurotransmitters and neuropeptides participate (Anctil et al., 1984; Lloyd & Willows, 1988; Ukena et al., 1995). In nematodes, cholinergic neurotransmission controls the chemosensory nerve output of the amphids, a pair of cephalic sensory organs, and pharangeal pumping is under cholinergic control (Croll, 1977).
Much of cholinergic neurotransmission is inhibitory, increasing Cl– or K+ conductances in postsynaptic neurons. This has been studied in detail in Aplysia (Kehoe, 1972a,b; Inoue et al., 1994; Kehoe & Vulfius, 2000; and many others).
ACh also activates muscarinic receptors associated with G proteins, although these are not well studied in invertebrates (Liu et al., 2016); most studies are in insects. Muscarinic receptors located presynaptically were found to inhibit release of ACh and other neurotransmitters in a form of negative feedback, whereas those located on the postsynaptic membrane induced excitatory responses both centrally and peripherally (Trimmer, 1995; Caulfield & Birdsall, 1998).
L-Glu is the fast excitatory neurotransmitter of the central nervous system of all Metazoa. This non-essential dietary amino acid is synthesized locally in neurons from glutamine by glutaminase. Another source is 2-oxoglutarate, an intermediate of the tricarboxylic acid cycle. L-Glu is taken up from the synaptic cleft by transporters in presynaptic terminals and glia. In vertebrate glia, L-Glu is converted into glutamine by glutamine synthetase for transport back to the presynaptic neuron, and there is scant evidence that this occurs in crustaceans (Sullivan et al., 2007).
As mentioned above, L-Glu is a critical neurotransmitter at the neuromuscular junction in all invertebrates. There is growing evidence that the iGluR subfamilies so important in vertebrates are also present in invertebrates, although the protein sequence similarity of putative NMDA-, AMPA- and kainite-like receptors to those of vertebrates is not sufficient for specific receptor effects to be isolated or defined with much precision. Nevertheless, L-Glu and its congeners such as NMDA and D-Asp have as widespread actions as ACh in excitable neurotransmission in invertebrates. Glutamatergic agonists cause contraction of striated muscle (Usherwood et al., 1984), and convey sensory information to central ganglia (Bravarenko et al., 2003; Kempsell & Fieber, 2015) among many other specific physiological actions.
L-Glu also can have inhibitory actions such as activation of Cl– conductances in pentameric ligand-activated receptors in nematodes and insects (Fuse et al., 2015).
The catecholamines DA, NE, and EPI all derive from tyrosine (Purves et al., 2001), as do OA and tyramine. As neurotransmitters, they are taken up from the synaptic cleft by Na+-dependent transporters. 5-HT is made from tryptophan. HA is made from histidine. Invertebrate amine neurotransmitters are primarily DA, OA, tyramine, HA, and 5-HT.
OA and tyramine are probably unique to invertebrates as neurotransmitters and hormones. OA acts analogously to vertebrate epinephrine and norepinephrine (Verlinden et al., 2010); all four are derived from tyrosine and thus chemically closely related. OA, at least, is enormously important with diverse actions. Tyramine is much less studied. Each has been most comprehensively studied in insects. They appear to activate G-protein-coupled receptors associated with stimulation or inhibition of adenylyl cyclase activity, Gs and Gi, respectively (Blenau & Baumann, 2001).
OA induces release of AKH from the central nervous system as well as induces release of fatty acids from the fat body, and thus it has a critical role in energy mobilization (Verlinden et al., 2010). It initiates the stress response as the fight-or-flight hormone of invertebrates (Blenau & Baumann, 2001). OA controls the activity of flight muscles. It increases the sensitivity of sensory receptors in the periphery through a complex of effects such as modifications of neuronal membrane resistance, adaptation of receptors to stimuli, enhancement of postsynaptic responsiveness, and the shape of the action potential. It also triggers ovulation and plays a critical role in olfactory conditioning in the honeybee.
In C. elegans, tyramine had a role in pathogenic avoidance learning (Jin et al., 2016). It has been suggested that tyramine may oppose the effects of OA by inhibiting adenylyl cyclase through a Gi-like receptor.
In the crustacean eye, NE, acting at α-adrenoreceptors, light-adapts distal retinal pigment by stimulating the release of light-adapting hormone, actions directly opposed by DA and its induction of dark-adapting hormone release (Fingerman et al., 1994). HA shepherds partially dark-adapted distal retinal pigments to their fully dark-adapted state by inhibiting the release of light-adapting hormone, while preventing partially light-adapted pigments from moving to fully light adapted (Stuart et al., 2007).
5-HT and OA, acting hormonally in release from the pericardial organ, a neurohemal structure, increase the crustacean heartbeat by modulating output of the cardiac ganglion; they also increase cardiac myocyte contractility. DA and NE act similarly in the heart, increasing heartbeat rate and amplitude via effects on cardiac ganglion neuronal bursting activity, stimulating or inhibiting different neurons. DA acts at Gs- and Gi-coupled receptors in this capacity, as well as in other actions in the NS (Blenau et al., 1998; Barbas et al., 2006). DA also affects heartbeat by modulating output of the interneurons the form the cardiac pacemaker. HA suppresses cardiac ganglion motor neuron activity by activating a chloride conductance.
The crustacean stomatogastric ganglion innervates the muscles of the foregut and is connected to the rest of the central nervous system via the stomatogastric nerve; its two groups of neurons control gastric mill muscular contractions and contractions of the pyloric stomach muscles, respectively. DA and to a lesser extent 5-HT and OA enhance nerve-evoked contractions of the foregut muscle. 5-HT modulates the pyloric muscle contraction rhythm by either postsynaptic or hormonal effects on the muscle. In Aplysia, DA- and 5-HT-mediated modulation of the buccal ganglia mediates ingestion and swallowing, respectively (Kabotyanski et al., 2000). Barbas et al. (2006) showed that 5-HT is a diversely acting molecule in invertebrates for which there are approximately five receptors in Aplysia, four in Drosophila, and three in C. elegans, with at least nine that can be classified with vertebrate 5-HT receptors; the rest have low similarity (Tierney, 2001). Serotonergic neurosecretory neurons dispense 5-HT into the lobster circulation to instigate agonistic behaviors, which are opposed by OA (Kravitz, 2000). Circulating 5-HT controls swimming behavior in the medicinal leech, Hirudo medicinalis, by activating the swim gating neurons (Kristan et al., 2005). 5-HT plays a large role in neural development in Drosophila and other insects (Blenau & Thamm, 2011).
5-HT induces dispersion of red, black, and/or white pigment in chromatophores in the crustacean cuticle; it acts as a neurotransmitter at 5-HT receptors to release red or black pigment movement hormones (RPDH and BPDH; Fingerman et al., 1994). DA acts either in mimic of these effects, or it inhibits them in some species, indirectly, like 5-HT, by controlling the release of pigment movement hormones. NE acts directly on melanophores via a-adrenoreceptors to disperse black pigment in the cuticle, while its effects on dispersing red pigment are via stimulation of release of RPDH. HA acting at H2 receptors inhibits BPDH release. OA also blocks release of BPDH.
5-HT and its precursor 5-hydroxytryptophan stimulate the release of MIH from the eyestalk X organ, culminating in suppression of ecdystone secretion from the Y organ (Fingerman et al., 1994). 5-HT and OA both partially block the release of methyl farnesoate from mandibular organs. 5-HT can stimulate ovarian development by triggering the release of gonad-stimulating hormone.
5-HT and OA acting hormonally activate a central motor program for postural flexion and postural extension in decapods, respectively, presumably by contrasting effects on the excitatory postsynaptic potential at the synapse of premotor interneurons with postural motor neurons (Fingerman et al., 1994). The amine neurotransmitters have numerous neuromuscular transmission effects in walking and swimming legs, and the tails and other appendages of decapods, but a uniting theme is that the receptors on motor neurons are usually for 5-HT, DA, NE, and OA.
In osmoregulatory control at the gills, DA and OA have contrasting effects on cAMP levels and thus effects on the Na-K-ATPase that acclimate euryhaline crustaceans to seawater (Fingerman et al., 1994). DA and 5-HT appear to control this process in acclimation to hypoosmotic environments.
5-HT mimics the effect of CHH in elevating hemolymph glucose, as do OA, NE, and EPI. Olfactory cells are rich in H2 receptors whose activation by HA suppresses activity. Some mechanoreceptors and stretch receptors in the appendages are sensitive to 5-HT and/or OA.
Finally, 5-HT plays strong roles in learning in Aplysia, mediating short-, intermediate-, and long-term memory of withdrawal reflexes (Bailey & Kandel, 2008; Lee et al., 2008; see also Chapter by Rankin on Nonassociative Learning in Invertebrates). Short-term memory induced by brief exposure to 5-HT is due to the modulation of a number of membrane currents (Byrne & Hawkins, 2015), one of which is a K+ current, whose reduction by PKA-dependent phosphorylation leads to depolarization and an increase in membrane excitability (Siegelbaum et al., 1982). 5-HT also activates protein kinase C, mobilizing transmitter and resulting in more release of neurotransmitter (L-Glu) into the synaptic cleft (Byrne & Hawkins, 2015). The overall effect is heightened excitability and increased neurotransmission using existing equipment in the synapse. Longer-term memory, induced by greater temporal exposure to 5-HT, on the other hand, involves new protein synthesis.
GABA and Glycine
GABA and glycine have reputations in the nervous system of both vertebrates and invertebrates as inhibitory neurotransmitters that activate ionic currents for chloride. GABA- and glycine-induced presynaptic inhibition are widespread phenomena in invertebrates (Gingl et al., 2004; Nishino et al., 2010). The axons of mechanosensory neurons in the periphery of the spider Cupiennius salei are especially vulnerable to GABA-induced inhibition, while in crustaceans stretch receptor neurons have GABAergic inhibition (Elekes & Florey, 1987). GABA can be excitatory at sensory neuron afferents in which the [Cl–] is high. Glycine can be a coagonist at excitatory NMDA receptors, although its high concentration in seawater makes this less likely in marine invertebrates (Carlson et al., 2012).
The purines ATP and adenosine, plus pyrimidines, are believed ancient signaling molecules coopted very early by the nervous system from their roles in energy production (Burnstock & Verkhratsky, 2009). ATP and its metabolites are present in presynaptic vesicles due to the necessity for active transport to concentrate neurotransmitter into the vesicle. Thus, ATP and adenosine are coagonists with other ligands, activating nonspecific cation channels, or Ca2+ channels, to induce modulatory, often excitatory effects. Their receptors often activate adenylyl cyclase-linked G proteins. Some of the wide-reaching effects of purinergic receptor activation are modulation of muscle (mollusks) and cilia movement (ctenophores, embryonic echinoderms), including modulation of cardiac contractility (mollusks, arthropods), repair of mechanoreceptors (cnidarians), olfaction and gustation (arthropods), axon regeneration (annelids), inhibition of sexual maturation (echinoderms), and control of luminescence (echinoderms). Adenosine often elicits an inhibitory effect when it binds to specific presynaptic receptors.
NO-mediated events are important in learning in gastropods (Kemenes et al., 2002; Susswein & Chiel, 2012; Korshunova & Balaban, 2014) and in long-term plasticity in Octopus ventral lobe (Shomrat et al., 2015). NO-induced plasticity may have been selected for in invertebrates (Moroz & Kohn, 2011) rather than, or in addition to, a system based on NMDA receptors for L-Glu, as in mammals (Shomrat et al., 2015).
We have been introduced to the idea that the Metazoan nervous system may have evolved multiple times, with species with disparate life histories and physiologies differently emphasizing the ways in which signals are communicated from neural command centers to the periphery and back again. We considered here just a few of the more than 70 neuropeptide families and the 10 or so broad classifications of smaller-molecule neurotransmitters available. This diversity of raw materials, combined with their broad spectrum of effects in different species, makes evident that ample methods exist for conducting the work of a nervous system in invertebrate animals. As Webster (2012) noted, the pleiotropic and overlapping effects of neuropeptides and neurotransmitters within a family constitute challenges to deducing the principal biological function of these signaling molecules in a species, let alone in a class or phylum. There is so much yet left to discover, with sensitive molecular and phylogenetic studies now outpacing the important confirmatory studies of receptor binding and physiological actions. The evolutionary focus of the genetic studies, fortuitously, however, has and will continue to allow reinterpretation of the findings of older studies in this newly supported context. The evolutionary focus is also an exciting perspective for new studies on established model animals. Invertebrate models of nervous system physiology will always offer insights on how the complexity of vertebrate nervous systems came into existence. With or without a sophisticated central nervous system, neuropeptides and neurotransmitters are the constants and the foundation of any number of evolved nervous system designs.
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