Established models of ternary complex formation between hormone, G protein coupled receptor (GPCR), and G protein assume that all interactions occur under equilibrium conditions. However, recent studies have established that the lifetimes of these interactions are comparable to the duration of hormone activated GPCR signaling. To simulate interactions during such non-equilibrium conditions, we propose a kinetic model wherein the receptor undergoes rate-limiting transitions between two hormone-bound active states. Simulations, using experimentally measured parameters, demonstrate transient states in ternary complex formation, and delineate the phenomenon of GPCR priming, wherein non-cognate G proteins substantially enhance cognate G protein signaling. Our model reveals that kinetic barriers of slow receptor interconversion can be overcome through allokairic modulation, a regulatory mechanism of ternary complex formation and downstream signaling.
Bibliographical noteFunding Information:
We would like to thank Dr. Danica Cui for helpful discussions on stopped-flow measurements. Research was supported by the NIH (R35-GM126940 to S.S. and 5K12GM119955-04 to K.J.C.) and the Science and Engineering Research Board grant (EMR/2017/003271 to C.J.G.).
© 2022, The Author(s).