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PAC1 Receptors: Shapeshifters in Motion

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Abstract

Shapeshifters, in common mythology, are entities that can undergo multiple physical transformations. As our understanding of G protein-coupled receptors (GPCRs) has accelerated and been refined over the last two decades, we now understand that GPCRs are not static proteins, but rather dynamic structures capable of moving from one posture to the next, and adopting unique functional characteristics at each transition. This model of GPCR dynamics underlies our current understanding of biased agonism—how different ligands to the same receptor can generate different intracellular signals—and constitutive receptor activity, or the level of unbound basal receptor signaling that can be attenuated by inverse agonists. From information derived from related class B receptors, we have recently modeled the structure and molecular dynamics of the full-length pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1)—selective PAC1 receptor (PAC1R, Adcyap1r1). The class B receptors are different from the class A GPCRs in part from the presence of a large extracellular domain (ECD); the transitions of the ECD along with the dynamics of the transmembrane domains (TMD or 7TM) of the PAC1R describes a series of open- and closed-state conformations that appear to identify the mechanisms for receptor activation. The PAC1R shapeshifts also have the ability of delineating the mechanisms and the design of reagents that may direct biased agonism (or antagonism) for potential therapeutics.

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Acknowledgements

We thank the UVM REACH grant for the support to this research. Computational resources were provided by Anton (PSC, NIH P41GM103712-S1), Stampede (XSEDE, NSF ACI-1053575), and Vermont Advanced Computing Core (VACC).

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Authors and Affiliations

  1. Department of Chemistry, University of Vermont, Discovery Hall, Burlington, VT, 05405, USA

    Chenyi Liao & Jianing Li

  2. Department of Neurological Sciences, University of Vermont Larner College of Medicine, 149 Beaumont Avenue, Burlington, VT, 05405, USA

    Victor May

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  1. Chenyi Liao
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  2. Victor May
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  3. Jianing Li
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Contributions

J. L. designed the studies and C. L. performed the simulations and analyzed the data. C. L., J. L. and V. M. wrote the paper; all of the authors contributed insights and critical edits to the final manuscript.

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Correspondence to Victor May or Jianing Li.

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Liao, C., May, V. & Li, J. PAC1 Receptors: Shapeshifters in Motion. J Mol Neurosci 68, 331–339 (2019). https://doi.org/10.1007/s12031-018-1132-0

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