CHAPTER 1
Evolutionary Aspects of Physiological Function and Molecular Diversity of the Oxytocin/Vasopressin Signaling System

Zita Liutkeviciute and Christian W. Gruber

Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

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 a-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 - covering not only the receptors and their cognate G proteins, but also upstream and downstream regulators of the system - 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 cell-cell 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 receptors and associated signaling molecules, which commonly belong to the family of G protein-coupled receptors. Many signaling peptides are released by the central nervous system and these neuropeptides are closely associated with the emergence of the first nervous system. Neuropeptides and the nervous system probably evolved in the common ancestor of cnidarians since sponges (the evolutionary older animal group) do not exhibit any physiological or anatomical signs of a nervous system. Neuropeptides are expressed in brains and are involved in the complex regulation of homeostatic processes and neuronal activity in metazoans. They may act as neurotransmitters, if released within synapses, or as neurohormones to activate receptors distal from the site of release. Neuropeptides are short (<50 amino acids) secreted polypeptides derived from larger precursor proteins which share defining features at the level of their primary sequence, which is useful for evolutionary studies, because short peptides sometimes lack sequence similarities (Mirabeau and Joly, 2013).

Recently, the evolutionary history of bilaterian neuropeptides and receptors was reconstructed to clarify the relationships between protostomian and deuterostomian peptidergic systems (Mirabeau and Joly, 2013). The results clearly indicated that the majority of peptidergic systems were present in the last common ancestor of bilaterians (the urbilaterian) (Table 1.1). This further supports the theory that the urbilaterian was an animal with a sophisticated physiology and a complex nervous system, capable of integrating sensory information. Another conclusion of this study was the existence of co-evolution between the majority of receptors and their ligands, although previously it has been suggested that, during evolution, novel ligands may outcompete existing ones for a given receptor (Mirabeau and Joly, 2013).

Table 1.1 Inferred evolutionary relationships between the different ancestral bilaterian peptidergic systems.

Mirabeau and Joly suggested that 29 peptidergic systems (here shown as different families from 1 to 29) were present in the last common ancestor of bilaterians (the urbilaterian). A dark gray square denotes the presence of both peptides and receptors from a given peptidergic system, a light gray square denotes the presence of receptor or peptide and the white square shows that both peptides and receptors are absent for a given peptidergic system in the phylogenetic group. Subphylum Vertebrata (V) is composed of Homo sapiens and Takifugu rubripes, phylum Tunicata (T) of Ciona intestinalis and Ciona savignyi, superphylum Ambulacraria (A) of Strongylocentrotus purpuratus and Saccoglossus kowalevskii, Lophotrochozoa (L) of Capitella teleta and Lottia gigantea, class Insecta (I) of Drosophila melanogaster, Tribolium castaneum, and Acyrthosiphon pisum, phylum Nematoda (N) of Caenorhabditis elegans and Pristionchus pacificus, Branchiostoma (B) of Branchiostoma floridae, and Daphnia (D) of Daphnia pulex (Mirabeau and Joly, 2013).

1.1.2 Origin of the oxytocin (OXT)/arginine vasopressin (AVP) signaling system

One of the best known peptidergic systems is OXT/AVP signaling. Homologs of OXT/AVP receptors and ligands have been identified in diverse organisms such as hydra, worms, insects, and vertebrates. Across evolutionary lineages, the OXT/AVP neuropeptide signaling system shows conserved functions in water homeostasis, reproductive behavior, learning, and memory (see section 1.4 later in this chapter) (Gruber, 2014).

Phylogenetic grouping indicated that invertebrate crustacean cardioactive peptide (CCAP) receptor, neuropeptide S (NPS) receptor, and AVP-like receptors form a monophyletic family which is phylogenetically the closest to the gonadotropin-releasing hormone (GnRH) receptor superfamily (Figure 1.1). Although CCAP, NPS, and AVP-like peptides are not similar in sequences, analyses of precursors encoding those peptides showed the presence of neurophysin domains in some of the genes, which consolidates the common origin of the peptides. Furthermore, AVP and neuropeptide S are found in neighboring tandem position in the amphioxus (Branchiostoma floridae) genome, indicating that they are the product of ancient duplication. Accordingly, in an ancestor of bilaterians, the duplication of a single gene (AVP/NPS/CCAP-like) must have occurred, which...