The role of G protein-coupled receptors in the early evolution of neurotransmission and the nervous system

Abstract

The origin and evolution of the nervous system is one of the most intriguing and enigmatic events in biology. The recent sequencing of complete genomes from early metazoan organisms provides a new platform to study the origins of neuronal gene families. This review explores the early metazoan expansion of the largest integral transmembrane protein family, the G protein-coupled receptors (GPCRs), which serve as molecular targets for a large subset of neurotransmitters and neuropeptides in higher animals. GPCR repertories from four pre-bilaterian metazoan genomes were compared. This includes the cnidarian Nematostella vectensis and the ctenophore Mnemiopsis leidyi, which have primitive nervous systems (nerve nets), the demosponge Amphimedon queenslandica and the placozoan Trichoplax adhaerens, which lack nerve and muscle cells. Comparative genomics demonstrate that the rhodopsin and glutamate receptor families, known to be involved in neurotransmission in higher animals are also widely found in prebilaterian metazoans and possess substantial expansions of rhodopsin-family-like GPCRs. Furthermore, the emerging knowledge on the functions of adhesion GPCRs in the vertebrate nervous system provides a platform to examine possible analogous roles of their closest homologues in pre-bilaterians. Intriguingly, the presence of molecular components required for GPCR-mediated neurotransmission in pre-bilaterians reveals that they exist in both primitive nervous systems and nerve-cell-free environments, providing essential comparative models to better understand the origins of the nervous system and neurotransmission. KEY WORDS: Neuron, GPCR, Nerve net, Synapse, EvolutionIntroduction G protein-coupled receptors (GPCRs) constitute the largest superfamily among membrane bound proteins that control key physiological functions, such as, neurotransmission, hormone releases, and immune responses among others (Katritch et al., 2013; Lagerström and Schiöth, 2008;Rosenbaum et al., 2009). As such, the large range of integral transmembrane proteins in this family respond to subsequent, diverse array of ligands: including neurotransmitters, hormones, lipids, and odorants (Civelli et al., 2013;Shoichet and Kobilka, 2012). GPCRs in mammals are classified into the five main families according to the GRAFS classification: glutamate, rhodopsin, adhesion, frizzled and secretin (Fredriksson et al., 2003). These five GPCR families are associated with various physiological functions, but the roles of the glutamate and the rhodopsin families are particularly well documented for REVIEW Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593,751 24, Uppsala, Sweden.*Authors for correspondence (arunkumar.krishnan@neuro.uu.se; helgi.schioth@neuro.uu.se) neurotransmission and regulation of the nervous system (Niswender and Conn, 2010;Schoepp, 2001). Some functions include synaptic transmission, synapse formation, axon guidance and development of neuronal circuits (Collingridge et al., 2004;Hnasko and Edwards, 2012)...

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Dual signaling of Wamide myoinhibitory peptides through a peptide‐gated channel and a GPCR in Platynereis

“…Release at neurohemal release sites allows neuropeptides to act as hormones in long-range signaling. The vast majority of neuropeptides signal through GPCRs and alter target cell physiology by metabotropic signals mediated by G proteins (3).…”

New paradigms in GPCR drug discovery

“…Residues occurring at the same relative position on TMs of different GPCRs can have conserved function, especially within the same GPCR family, but the shape and orientation of the ligand binding site can vary widely within the upper portion of the receptor. There are two systems for classifying GPCR sequences: The GRAFS system has five categories: Glutamate; R hodopsin; A dhesion; F rizzled; T aste2; S ecretin, based purely on phylogeny rather that ligand similarity [153]. Alternatively, the IUPHAR system has six categories (A through F), some of which correspond to individual GRAFS categories.…”

“…Alternatively, the IUPHAR system has six categories (A through F), some of which correspond to individual GRAFS categories. The three families most relevant to drug discovery are: A (rhodopsin-like), B (secretin-related) and C (glutamate/GABA-related), and their early evolution has been studied [153]. A database listing >500,000 experimentally-validated GPCR-ligand associations is available on the web [37].…”