Title:Targeting the PAC1 Receptor for Neurological and Metabolic Disorders
Volume: 19
Issue: 16
Author(s): Chenyi Liao, Mathilde P. de Molliens, Severin T. Schneebeli, Matthias Brewer, Gaojie Song, David Chatenet, Karen M. Braas, Victor May*Jianing Li*
Affiliation:
- Department of Neurological Sciences, University of Vermont, Larner College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405,United States
- Department of Chemistry, University of Vermont, Burlington, VT 05405,United States
Keywords:
Class B GPCR, Behavioral disorders, Neurodegenerative diseases, Molecular modeling, Structure-based drug discovery,
PAC1 Receptor.
Abstract: The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor
(PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family
of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central
and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction
pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regulate
a number of physiological systems to maintain functional homeostasis. Accordingly, at times of
tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay
apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the
potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration
(such as Parkinson’s and Alzheimer's disease), or peripheral organ insults. Conversely,
maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stressrelated
psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities),
chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological
conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated
biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we
first describe the current knowledge regarding the molecular structure, dynamics, and function of
PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling
cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug
design and development of peptides and small molecules targeting PAC1R based on a number of structure-
activity relationship studies and key pharmacophore elements. At present, the rational design of
PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural
information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core
segments involved in receptor activation. Understanding the molecular basis governing the PACAP
interactions with its different cognate receptors will undoubtedly provide a basis for the development
and/or refinement of receptor-selective therapeutics.