Abstract
Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. A small number of known active compounds for these receptors still impose limitations on their use in therapeutics. Recent cryo-EM structures of VPAC1 and PAC1 receptors in their agonist-bound active state have provided insights regarding their mechanism of activation. Here, we describe major molecular switches of VPAC1, VPAC2, and PAC1 that may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. The impact of genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists is also described. This sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors.
Highlights
Publisher’s Note: MDPI stays neutralVPAC1, VPAC2, and PAC1 receptors are secretin-like G protein-coupled receptors, constituting one of five main GPCR classes regulating responses to extracellular stimuli in humans
Among class B GPCRs, VPAC1, VPAC2, and PAC1 receptors are known for their role in smooth muscle relaxation and regulation of exocrine and endocrine secretions
Interactions between VPAC1 and Gαi were demonstrated and it was confirmed that the VPAC1-mediated [Ca2+ ]i increase is not affected by the chelation of extracellular calcium [69], whilst the pertussis toxin (PTx)-sensitive activation of phospholipase C (PLC) by VPAC2 relies on a Gβγ-dependent mechanism and on Ca2+ entry through receptor-operated Ca2+ channels [68]
Summary
VPAC1, VPAC2, and PAC1 receptors are secretin-like G protein-coupled receptors, constituting one of five main GPCR classes regulating responses to extracellular stimuli in humans. Among class B GPCRs, VPAC1, VPAC2, and PAC1 receptors are known for their role in smooth muscle relaxation and regulation of exocrine and endocrine secretions. They are activated by two related neuropeptides [7,8], vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) of common, helical conformations [9,10,11]. PAC1 is involved in diverse biological processes as its agonist PACAP acts as a neurotransmitter in regulating hormone secretion (adrenaline, insulin, growth hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, and adrenocorticotropic hormone), tear secretion, vasodilation, and immunosuppression It is involved in neuroprotection in case of cerebral brain ischemia, Parkinson’s disease, spinal injury, etc. 10 clinical trials involving PACAP27/PACAP-38/VIP have been completed, out of which nine were associated with migraine while one involved nephrotic syndrome
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