Charge Movements and Conformational Changes: Biophysical Properties and Physiology of Voltage-Dependent GPCRs

G protein-coupled receptors (GPCRs) regulate multiple cellular functions and represent important drug targets. More than 20 years ago, it was noted that GPCR activation (agonist binding) and signaling (G protein activation) are dependent on the membrane potential (V_M). While it is now proven that many GPCRs display an intrinsic voltage dependence, the molecular mechanisms of how GPCRs sense depolarization of the plasma membrane are less well defined. This review summarizes the current knowledge of voltage-dependent signaling in GPCRs. We describe how voltage dependence was discovered in muscarinic receptors, present an overview of GPCRs that are regulated by voltage, and show how biophysical properties of GPCRs led to the discovery of voltage-sensing mechanisms in those receptors. Furthermore, we summarize physiological functions that have been shown to be regulated by voltage-dependent GPCR signaling of endogenous receptors in excitable tissues, such as the nervous system or the heart. Finally, we discuss challenges that remain in analyzing voltage-dependent signaling of GPCRs in vivo and present an outlook on experimental applications of the interesting concept of GPCR signaling.