Optical Control of P2X Receptors

[Speaker] Thomas Grutter:1,2
1:University of Strasbourg, France, 2:CNRS, France

P2X receptors are ligand-gated ion channels activated by extracellular ATP. There are seven P2X receptor subtypes in mammals (P2X1 to P2X7) that assemble to form functional homo or hetero trimeric cation-selective channels. P2X receptors contribute to many important physiological processes, including the modulation of neurotransmitter release, hearing protection, male fertility, the response to inflammation and pain sensation. They are also involved in severe disorders, such as neuropathic pain and are thus recognized as important therapeutic targets. Recent X-ray structures of P2X receptors solved in resting, open-channel, and desensitized states have greatly advanced our understanding of agonist binding and channel gating. However, despite these significant biophysical advances, there is still a lack of specific pharmacological tools targeting P2X receptors. Recent developments of optogenetics offer great opportunities for the optical control of channel activation, with exquisite temporal and spatial resolution. Inspired by these achievements, we have developed new and versatile approaches, called optogating and opto-tweezers, in which the gating machinery of the P2X2 receptor was reprogrammed to respond to light. We demonstrated photocontrol of neuronal activity by a light-gated P2X receptor, in which the natural sensitivity to ATP was genetically removed. We also uncovered part of the gating mechanism and ion permeation of P2X receptors using these optical actuators. Engineered light-gated purinergic receptors represent valuable tools for investigating P2X signaling in native tissues.
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