The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications

In the landscape of proteins controlled by membrane voltage (V_m), like voltage-gated ionotropic channels, the emergence of the voltage sensitivity within the vast family of G-protein coupled receptors (GPCRs) marked a significant milestone at the onset of the 21st century. Since its discovery, extensive research has been devoted to understanding the intricate relationship between V_m and GPCRs. Approximately 30 GPCRs out of a family comprising more than 800 receptors have been implicated in V_m-dependent positive and negative regulation. GPCRs stand out as the quintessential regulators of synaptic transmission in neurons, where they encounter substantial variations in V_m. However, the molecular mechanism underlying the V_m sensor of GPCRs remains enigmatic, hindered by the scarcity of mutant GPCRs insensitive to V_m yet functionally intact, impeding a comprehensive understanding of this unique property in physiology. Nevertheless, two decades of dedicated research have furnished numerous insights into the molecular aspects of GPCR V_m-sensing, accompanied by recently proposed physiological roles as well as pharmacological potential, which we encapsulate in this review. The V_m sensitivity of GPCRs emerges as a pivotal attribute, shedding light on previously unforeseen roles in synaptic transmission and extending beyond, underscoring its significance in cellular signaling and physiological processes.