A paradigm shift in GPCR recruitment and activity: GPCR Voltage Dependence Controls Neuronal Plasticity and Behavior

G-protein coupled receptors (GPCRs) play a paramount role in diverse brain functions. Almost 20 years ago, GPCR activity was shown to be regulated by membrane potential in vitro, but whether the voltage dependence of GPCRs contributes to neuronal coding and behavioral output under physiological conditions in vivo has never been demonstrated. We show that muscarinic GPCR mediated neuronal potentiation in vivo is voltage dependent. This potentiation voltage dependency is abolished in mutant flies expressing a voltage independent receptor. We further show that depolarization alone, without a muscarinic agonist, was sufficient to recruit and activate the muscarinic GPCR. Most important, muscarinic receptor voltage independence caused a strong behavioral effect of increased odor habituation. Thus, this study provides the very first demonstration of a physiological role for the voltage dependency of GPCRs by demonstrating crucial involvement of GPCR voltage dependence in neuronal plasticity and behavior. As such, these findings create a paradigm shift in our thinking on GPCR recruitment and activity. Together, this study suggests that GPCR voltage dependency plays a role in many diverse neuronal functions including learning and memory and may serve as a target for novel drug development.