Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is a well-conserved neuropeptide characteristic of vertebrates. This pluripotent hypothalamic neuropeptide regulates neurotransmitter release, intestinal motility, metabolism, cell division/differentiation, and immunity. In vertebrates, PACAP has a specific receptor (PAC1) but it can also activate the Vasoactive Intestinal Peptide receptors (VPAC1 and VPAC2). The evolution of the vertebrate PACAP ligand – receptor pair has been well-described. In contrast, the situation in invertebrates is much less clear. The PACAP ligand – receptor pair in invertebrates has mainly been studied using heterologous antibodies raised against mammalian peptides. A few partial PACAP cDNA clones sharing >87% aa identity with vertebrate PACAP have been isolated from a cnidarian, several protostomes and tunicates but no gene has been reported. Moreover, current evolutionary models of the peptide and receptors using molecular data from phylogenetically distinct invertebrate species (mostly nematodes and arthropods) suggests the PACAP ligand and receptors are exclusive to vertebrate genomes. A basal deuterostome, the cephalochordate amphioxus (Branchiostoma floridae), is the only invertebrate in which elements of a PACAP-like system exists but the peptides and receptor share relatively low sequence conservation with the vertebrate homolog system and are a hybrid with the vertebrate glucagon system. In this study, the evolution of the PACAP system is revisited taking advantage of the burgeoning sequence data (genome and transcriptomes) available for invertebrates to uncover clues about when it first appeared. The results suggest that elements of the PACAP system are absent from protozoans, non-bilaterians, and protostomes and they only emerged after the protostome-deuterostome divergence. PACAP and its receptors appeared in vertebrate genomes and they probably shared a common ancestral origin with the cephalochordate PACAP/GCG-like system which after the genome tetraploidization events that preceded the vertebrate radiation generated the PACAP ligand and receptor pair and also the other members of the Secretin family peptides and their receptors.
Highlights
The pituitary adenylate cyclase-activating polypeptide (PACAP) is one of the most extensively studied neuropeptides due to its biomedical interest and its well-conserved functions in vertebrates
To date the only invertebrate PACAP/GCG-like receptor isolated and functionally characterized is from the cephalochordate, amphioxus (Branchiostoma floridae) but this receptor shares poor sequence similarity (37% aa identity) with the vertebrate PAC1 but when it is activated it triggers intracellular signaling processes similar to the mammalian homolog (On et al, 2015)
A PACAP-like receptor similar to that in vertebrates was previously predicted in an annelid, Eisenia fetida and in the gastropods, Lymnaea stagnalis and Helix pomatia based on protein detection with heterologous antisera raised against the homolog mammalian receptor
Summary
The pituitary adenylate cyclase-activating polypeptide (PACAP) is one of the most extensively studied neuropeptides due to its biomedical interest and its well-conserved functions in vertebrates. In vertebrates’ receptors that are activated by PACAP are member of family B1 GPCRs. To date the only invertebrate PACAP/GCG-like receptor (bf95) isolated and functionally characterized is from the cephalochordate, amphioxus (Branchiostoma floridae) but this receptor shares poor sequence similarity (37% aa identity) with the vertebrate PAC1 but when it is activated it triggers intracellular signaling processes similar to the mammalian homolog (On et al, 2015). To provide evidence supporting the existence of a non-vertebrate homolog of vertebrate PAC1 and to further understand how the peptide-receptor system emerged we searched for putative receptor sequence homologs in representative species of major invertebrate phyla and compared receptor evolution to that of other family B1 GPCRs. In protostomes, a PACAP-like receptor similar to that in vertebrates was previously predicted in an annelid, Eisenia fetida and in the gastropods, Lymnaea stagnalis and Helix pomatia based on protein detection with heterologous antisera raised against the homolog mammalian receptor. In the Ciona genome two sequence homologs of the vertebrate GCGR-subfamily were retrieved, but a putative PACAP receptor gene was absent (Supplementary Figure 1)
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