GPCR voltage dependence controls neuronal plasticity and behavior

Eyal Rozenfeld,Merav Tauber,Moshe Parnas,Yair Ben-Chaim

doi:10.1038/s41467-021-27593-x

Eyal Rozenfeld, Merav Tauber + Show 2 more

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https://doi.org/10.1038/s41467-021-27593-x

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Abstract

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. Here we show that muscarinic GPCR mediated neuronal potentiation in vivo is voltage dependent. This voltage dependent potentiation is abolished in mutant animals expressing a voltage independent receptor. Depolarization alone, without a muscarinic agonist, results in a nicotinic ionotropic receptor potentiation that is mediated by muscarinic receptor voltage dependency. Finally, muscarinic receptor voltage independence causes a strong behavioral effect of increased odor habituation. Together, this study identifies a physiological role for the voltage dependency of GPCRs by demonstrating crucial involvement of GPCR voltage dependence in neuronal plasticity and behavior. Thus, this study suggests that GPCR voltage dependency plays a role in many diverse neuronal functions including learning and memory.

Highlights

G-protein coupled receptors (GPCRs) play a paramount role in diverse brain functions
GPRC voltage dependence was shown to control synaptic release initiation and duration in vitro[17,18,19,20,21,22], there is no evidence that these small changes in the duration of synaptic release affect neuronal computation or behavioral output, especially in the background of noisy neural activity
When the membrane potential is depolarized, mAChR-A is in a high activity state, and when the membrane potential is hyperpolarized, it is in a low activity state

Summary

Introduction

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. Over 90% of non-sensory GPCRs are expressed in the brain, where they mediate responses to various biologically active molecules including acetylcholine, glutamate, dopamine, noradrenaline, serotonin, histamine, GABA, peptides, lipid-derived products, and to mechanical stimuli[2,3] As such, they play a paramount role in diverse brain functions, for example, vision, taste, olfaction, behavior regulation, neuromodulation, and regulation of the immune system among others. Despite several decades of research into the functions of GPCRs, it is still not clear whether GPCR voltage dependency plays a role in vivo under physiological conditions or contributes to neuronal coding and behavioral output. Manipulation of Drosophila muscarinic receptors results in profound physiological and behavioral effects[23,28], which makes, the Drosophila olfactory system well suited to examine whether GPCR voltage dependence affects physiological processes and behavior

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