1.1 Evolution of peptidergic signaling
One of the major eukaryotic signal transduction machineries is composed of G protein-coupled receptors (GPCRs) and their associated signaling molecules (see Chapter 10). GPCRs share a seven Ī±-helical transmembrane architecture with an extracellular N-terminus and an intracellular C-terminus, and are able to sense a diverse set of ligand molecules, including proteins, peptides, amino acids, nucleosides, nucleotides, ions, and photons. GPCRs are involved in many processes such as cell growth, migration, density sensing or neurotransmission (Gruber et al., 2010).
Proteins comprising a seven-transmembrane topology have been identified as far back in the evolutionary timeline as prokaryotes; these are, for instance, light-sensitive proteo-, bacterio- and halorhodopsin proteins that are involved in non-photosynthetic energy harvesting in Archaea and bacteria. Structurally similar sensory rhodopsin proteins can also be found in eukaryotes, but to determine the phylogenetic relationship between prokaryotic and eukaryotic GPCRs is rather difficult, since (i) the prokaryotic and eukaryotic proteins have evolved independently for approximately 1.2 billion years, which resulted in low sequence conservation, and (ii) the occurrence of lateral gene transfer between prokaryotes and eukaryotes has been reported for certain microbial rhodopsins, which further complicates the analysis of phylogenic relations (Strotmann et al., 2011).
Recent studies on the evolution of GPCR signaling systems in eukaryotes ā covering not only the receptors and their cognate G proteins, but also upstream and downstream regulators of the system ā concluded that the last eukaryotic common ancestor must have already expressed a complex repertoire of GPCRs. Furthermore, it has been suggested that different parts of the GPCR signaling system evolved independently, and that some of them have been lost or became simplified without disrupting overall signaling functionality. For instance, most organisms contain most of the known GPCR signaling components, but certain species have retained only a subset of those, whereas others are completely reduced. These findings suggest that the GPCR signaling system is modular and that during evolution, drastic rearrangements can occur without complete loss of functionality. Analyses of protein domain architectures additionally suggest that domain shuffling is a major mechanism of signaling system evolution (de Mendoza et al., 2014).
Gene families and protein domain architectures of cytoplasmic transduction elements (for example, G proteins, arrestins, regulators of G protein signaling, guanine nucleotide exchange factors) are largely conserved between unicellular holozoans and metazoans. In contrast, receptors underwent a dramatic expansion in metazoans compared to their closest unicellular relatives. For instance, the human and mouse genomes code for more than 800 and 1300 GPCRs, respectively, which equals more than 1% of the total predicted genes, while yeast has as little as 10 GPCR genes, less than 0.2% of the total predicted genes (de Mendoza et al., 2014; Fredriksson and Schioth, 2005). This could be due to adaptation of GPCR signaling systems for new functions, such as cellācell communication, developmental control, and complex environmental sensing, from light to odor and taste (de Mendoza et al., 2014). However, most GPCRs do not play a primary vital role in these organisms. Only 8% of GPCR genes in mice responded to gene disruption by embryonic or perinatal lethality; about 41% exhibited an obvious phenotype and more than 50% of knockout mice of individual GPCRs display no obvious phenotypical change (Schoneberg et al., 2004). However, in humans, mutations in genes encoding GPCRs and G proteins result in pathological conditions, for instance severe vision impairment and blindness, and many other retinal, endocrine, metabolic or developmental disorders (Schoneberg et al., 2004).
1.1.1 Evolution and diversity of peptide G protein-coupled receptors and their endogenous ligands
Of particular interest for this chapter are peptidergic systems, which are generally defined as a functional complex consisting of a cell that synthesizes and releases a peptide mediator, a cell that responds to that peptide by a certain physiological change, and the process of transferring the peptide from the site of synthesis to the site of action. In particular, we use the term peptidergic signaling for pathways that are mediated by peptides, their endogenous re...
