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VIP and PACAP, originating from a shared primordial peptide-encoding gene in vertebrates, have an intertwined evolutionary history through two whole-genome duplications inherited by mammals. Based on their binding affinities they also share three structurally and evolutionarily related receptors. This review provides a brief history of VIP and PACAP, the peptides co-encoded with PACAP and VIP within their prohormone precursor proteins, and the PACAP, VIP, PACAP-related peptide (PRP) and VIP-related peptide (VRP/PHM/PHI) receptors. These are embedded within the growth hormone-releasing hormone/secretin division of the secretin superfamily of peptides and receptors which also includes the endocrine peptide-receptor dyads comprising the CRH/urocortin 1–3, calcitonin/CGRP/adrenomedullin (ADM)/amylin (IAPP), parathyroid hormone/TIP39 and GIP/glucagon/GLP-1/glucagon-related peptide subfamilies. Our review emphasizes four main points about the PACAP/VIP peptide signalling system. First, while PACAP and VIP and their receptors display evolutionary interdependence, evolutionary pressures on ligands and receptors are not perfectly aligned. Second, evolution of peptide and receptor structure and function is also linked to the evolution of broader cellular features such as prohormone production, processing, vesicular packaging and G-protein-coupling mechanisms. Therefore, functional deductions cannot rely solely on paralogous lineages or amino acid sequences. Third, the evolution of neuropeptides and their expanding functions, from hormone to paracrine factor to neurotransmitter, involves intricate control of peptide and receptor gene expression by cell-specific transcription factors. Fourth, understanding PACAP and VIP evolution offers insights into conservation of function, particularly within mammals, which can inform translational research for peptide-based therapeutics in humans. These might also be provisionally applied to other neuropeptides, including glucagon, GIP, secretin, CRH, GRP, calcitonin, CGRP, TIP39, adrenomedullin and amylin, that interact with family B1G-protein-coupled receptors.

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Co-evolution of PACAP, VIP and Related Peptides and Their Receptors as Neuroendocrine Signalling Dyads in Vertebrates

  • 章节

  • 发表日期：

    2025年

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  • Limei Zhang,
  • Vito Hernandez,
  • Lee E. Eiden

摘要

VIP and PACAP, originating from a shared primordial peptide-encoding gene in vertebrates, have an intertwined evolutionary history through two whole-genome duplications inherited by mammals. Based on their binding affinities they also share three structurally and evolutionarily related receptors. This review provides a brief history of VIP and PACAP, the peptides co-encoded with PACAP and VIP within their prohormone precursor proteins, and the PACAP, VIP, PACAP-related peptide (PRP) and VIP-related peptide (VRP/PHM/PHI) receptors. These are embedded within the growth hormone-releasing hormone/secretin division of the secretin superfamily of peptides and receptors which also includes the endocrine peptide-receptor dyads comprising the CRH/urocortin 1–3, calcitonin/CGRP/adrenomedullin (ADM)/amylin (IAPP), parathyroid hormone/TIP39 and GIP/glucagon/GLP-1/glucagon-related peptide subfamilies. Our review emphasizes four main points about the PACAP/VIP peptide signalling system. First, while PACAP and VIP and their receptors display evolutionary interdependence, evolutionary pressures on ligands and receptors are not perfectly aligned. Second, evolution of peptide and receptor structure and function is also linked to the evolution of broader cellular features such as prohormone production, processing, vesicular packaging and G-protein-coupling mechanisms. Therefore, functional deductions cannot rely solely on paralogous lineages or amino acid sequences. Third, the evolution of neuropeptides and their expanding functions, from hormone to paracrine factor to neurotransmitter, involves intricate control of peptide and receptor gene expression by cell-specific transcription factors. Fourth, understanding PACAP and VIP evolution offers insights into conservation of function, particularly within mammals, which can inform translational research for peptide-based therapeutics in humans. These might also be provisionally applied to other neuropeptides, including glucagon, GIP, secretin, CRH, GRP, calcitonin, CGRP, TIP39, adrenomedullin and amylin, that interact with family B1G-protein-coupled receptors.