Tracing the Origins of the Pituitary Adenylate-Cyclase Activating Polypeptide (PACAP)

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 (PAC 1) but it can also activate the Vasoactive Intestinal Peptide receptors (VPAC 1 and VPAC 2). 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.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review

“…PACAP is encoded by the ADCYAP1 gene located on chromosome 18, which has four exons. Exon 4 encodes PACAP and originates two biologically active peptide isoforms [2]. PACAP-38-consisting of 38 amino acids and is C-terminally α-amidated.…”

“…PACAP-38-consisting of 38 amino acids and is C-terminally α-amidated. PACAP-27-is the result of post-translational processes in which it is shortened at the C-terminus, keeping the same amino acid sequence at the N-terminus [2,3]. Previous studies have shown that PACAP-38 is the dominant form in mammals [3].…”

PACAP/GCGa Is an Important Modulator of the Amphioxus CNS-Hatschek’s Pit Axis, the Homolog of the Vertebrate Hypothalamic-Pituitary Axis in the Basal Chordates

“…Recently, peptides that have shared common ancestral origin with the vertebrate hypothalamic-pituitary adenylate cyclase-activating polypeptide/glucagon-like peptide (PACAP/GCGs) superfamily (aka as the secretin peptide family) which emerged and expanded during the two rounds of whole genome duplication were described in amphioxus ( 12 , 13 ). In the cephalochordate Branchiostoma floridae , a single PACAP/GCG gene that encodes for 3 mature peptides (PACAP/GCGa, GCGb, and GCGc) that are similar in sequence was described, but they share only marginal sequence similarity for the vertebrate orthologs; however, key amino acid residues that are important for receptor function are present ( 14 – 16 ).…”

“…In vertebrates, PACAP/GCG peptides activate receptors of class B1 of the G-protein coupled receptor (GPCR, aka Secretin GPCRs) superfamily, and in B. floridae , a functional PACAP/GCG receptor ( PACAP/GCG-R ) has been characterized ( 12 ). In other amphioxi species, homologs exist, but their physiological role remains to be established ( 13 ). In other invertebrates such as tunicates (urochordate) and few protostomes (arthropods, mollusc, and planarian), putative peptides that share higher sequence similarity for the vertebrate PACAP peptide have been described, but their existence remains yet to be confirmed ( 13 , 17 , 18 ).…”

“…In other amphioxi species, homologs exist, but their physiological role remains to be established ( 13 ). In other invertebrates such as tunicates (urochordate) and few protostomes (arthropods, mollusc, and planarian), putative peptides that share higher sequence similarity for the vertebrate PACAP peptide have been described, but their existence remains yet to be confirmed ( 13 , 17 , 18 ).…”