Abstract
In the landscape of proteins controlled by membrane voltage (Vm), 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 Vm and GPCRs. Approximately 30 GPCRs out of a family comprising more than 800 receptors have been implicated in Vm-dependent positive and negative regulation. GPCRs stand out as the quintessential regulators of synaptic transmission in neurons, where they encounter substantial variations in Vm. However, the molecular mechanism underlying the Vm sensor of GPCRs remains enigmatic, hindered by the scarcity of mutant GPCRs insensitive to Vm 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 Vm-sensing, accompanied by recently proposed physiological roles as well as pharmacological potential, which we encapsulate in this review. The Vm 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.