Paper

Toward a first principles understanding of the activation and deactivation mechanisms of class A G-protein coupled receptors and voltage-gated cation channels

Wan, Hongbin, Pearlstein, Robert Alan

2022

Overview

We previously reported a first principles multi-scale theory called Biodynamics that attributes cellular functions to sets of coupled molecular and ionic fluxes operating in the non-equilibrium/non-linear dynamic regime. Fluxes build and decay over time and undergo dynamic non-covalent intra- and intermolecular state transitions powered principally by the storage and release of free energy to/from the H-bond networks of external and internal solvation (that we refer to as solvation dynamics) at rates governed by the desolvation and resolvation costs incurred during their entry and exit, respectively. We have thus far examined the functional state transitions of cereblon and COVID Mpro in this context, and now turn to the agonist-induced activating and deactivating state transitions of class A G-protein coupled receptors (GPCRs) and membrane potential-/dipole potential-induced activating and deactivating state transitions of voltage-gated cation channels (VGCCs). We analyzed crystal structures of the activated and deactivated forms of the human β2 adrenergic receptor (β2AR) and cryo-EM structures of the activated and deactivated forms of Nav1.7 channels. We postulate that activation and deactivation of the β2AR is conveyed by switchable changes in transmembrane helix (TMH) orientations relative to extracellular loop 2 (ECL2) and curvature of TMH6 and TMH7, all of which are powered by solvation free energy and kickstarted by agonist binding. The known activation and deactivation mechanisms of Nav1.7 consist of S4 translations toward and away from the extracellular membrane surface, respectively, resulting in S4-S5 linker repositioning, followed by rearrangements of the S5 and S6 helices. The latter TMH conveys channel opening and closing by respectively curving away from and toward the central pore axis. We postulate that all of these rearrangements are likewise powered by solvation free energy and kickstarted by changes in the membrane and dipole potentials. The results of our study may facilitate structure-based design of GPCR agonists/antagonists and mitigation of drug-induced ion channel blockade. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Adrenergic receptors / Agonists / Antagonists / Calcium channels (voltage-gated) / Channel opening / Deactivation / Drug development / Free energy / G protein-coupled receptors / Membrane potential / Pharmacology and Toxicology / Sodium channels (voltage-gated)