Unravelling the Physiological Roles of GPCR Voltage Dependence

Introduction

G protein coupled receptors (GPCRs) are broadly expressed in the brain, mediate responses to many molecules, and are crucial for normal brain function and therapeutic intervention.

Background

Twenty years ago, it was shown that the activity of many GPCRs is regulated by membrane potential. For example, the activity of cholinergic M2R muscarinic and metabotropic glutamate mGluR3 receptors is reduced by depolarization, while that of M1R and mGluR1a is increased. However, due to high technical challenges, a crucial question remains unanswered: what are the physiological roles of this voltage dependency, its effect on neural activity, or its relevance to behavior?

Recent Findings

Recently, we showed that M1R voltage dependence is crucial for its recruitment. Under physiological conditions, in vivo, M1R could not be activated without depolarization; depolarization alone was sufficient to activate M1R. Furthermore, flies with a voltage-independent M1R had increased odor habituation, indicating a paramount effect on behavior. These findings are pivotal in our thinking on GPCR recruitment and activity.

Future Directions

To create a real paradigm shift, we need to unravel whether GPCR voltage dependence has a role in other types of GPCRs and neuronal processes.

Model System

The fly is an ideal model system to explore GPCR voltage dependence roles because it has a low variety of receptors with no functional overlap. In particular, the Drosophila dopaminergic and muscarinic receptors that are highly expressed in the olfactory system seem ideal.

Methodology

I will use a multidisciplinary approach of:

1. Electrophysiology
2. Two-photon imaging
3. Genetics
4. Behavior

This approach will examine GPCR voltage dependency and means to manipulate it, unravel these GPCR physiological roles, and investigate whether abolishing GPCR voltage dependence affects neuronal activity and behavioral output.

Conclusion

The understanding that there is a “voltage rheostat” that controls GPCR activity will open an entirely new field of research and can serve for new therapeutic intervention.