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Signal Transduction by VIP and PACAP Receptors.
Ingrid Langer1, Jérôme Jeandriens1, Alain Couvineau2
1Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles, B-1070 Brussels, Belgium.
Biomedicines
|February 25, 2022
Summary
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling through their receptors are crucial for immune homeostasis. Understanding their molecular switches can lead to novel therapies for inflammation, cancer, and neuroprotection.
Area of Science:
- Neuroimmunology
- Molecular Pharmacology
- Structural Biology
Background:
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides regulating immune homeostasis, intestinal function, and endocrine signaling.
- These peptides act via three Class B G protein-coupled receptors: VPAC1, VPAC2, and PAC1.
- Targeting these receptors offers potential therapeutic strategies for chronic inflammation, cancer, and neurodegenerative diseases.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the activation of VPAC1, VPAC2, and PAC1 receptors.
- To compare the activation switches of VIP and PACAP receptors with those of other GPCRs.
- To provide a molecular basis for designing novel, selective drugs targeting these receptors.
Main Methods:
- Analysis of recent cryo-electron microscopy (cryo-EM) structures of agonist-bound VPAC1 and PAC1 receptors.
- Identification and comparison of key molecular switches and interhelical interactions within VIP and PACAP receptors.
- Examination of the impact of genetic variants on receptor signaling.
Main Results:
- Detailed description of major molecular switches in VPAC1, VPAC2, and PAC1 receptors that trigger activation.
- Comparison of these switches with activation-associated conformational changes in other GPCRs.
- Identification of interhelical interactions crucial for agonist binding and receptor activation.
Conclusions:
- Structural insights into VIP and PACAP receptor activation provide a foundation for developing targeted therapeutics.
- Novel selective drugs targeting these receptors could yield anti-inflammatory, anti-cancer, and neuroprotective effects.
- Genetic variations in VIP, PACAP, and their receptors significantly influence signaling, agonist selectivity, and potency.
Keywords:
G protein-coupled receptorsPAC1VPAC1VPAC2class Bgene co-occurrencemicroswitchesneuropeptidespituitary adenylate cyclase activating polypeptidereceptor activationsecretin-like GPCRssequence conservationsplice variantssplicingvasoactive intestinal polypeptideMore Related Videos
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