Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors

Jessica Lu, Sarah J. Piper, Peishen Zhao, Laurence J. Miller, Denise Wootten, Patrick M. Sexton

Research output: Contribution to journalReview articlepeer-review


Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and pathological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors (GPCRs): VIP receptor 1 (VPAC1R), VIP receptor 2 (VPAC2R), and PACAP type I receptor (PAC1R). VIP and PACAP share nearly 70% amino acid sequence identity, while their receptors PAC1R, VPAC1R, and VPAC2R share 60% homology in the transmembrane regions of the receptor. PACAP binds with high affinity to all three receptors, while VIP binds with high affinity to VPAC1R and VPAC2R, and has a thousand-fold lower affinity for PAC1R compared to PACAP. Due to the wide distribution of VIP and PACAP receptors in the body, potential therapeutic applications of drugs targeting these receptors, as well as expected undesired side effects, are numerous. Designing selective therapeutics targeting these receptors remains challenging due to their structural similarities. This review discusses recent discoveries on the molecular mechanisms involved in the selectivity and signaling of the PACAP subfamily of receptors, and future considerations for therapeutic targeting.

Original languageEnglish (US)
Article number8069
JournalInternational journal of molecular sciences
Issue number15
StatePublished - Aug 2022


  • GPCR
  • PACAP type I receptor (PAC1R)
  • peptide therapeutics
  • pituitary adenylate cyclase-activating polypeptide (PACAP)
  • receptor selectivity
  • structure-based drug design
  • vasoactive intestinal peptide (VIP)
  • VIP receptor 1 (VPAC1R)
  • VIP receptor 2 (VPAC2R)

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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