Optogenetic and optical probing of potassium channel Physiology

Orateur : Guillaume SANDOZ (Institute of Biology Valrose CNRS UMR7277, INSERM U1091, Université Nice-Sophia Antipolis)

Ion channels generate the electrical signals with which the nervous system senses the world, processes information, creates memories and controls behavior. One of the most diverse and important families of ion channels, the K2P channels, serves as a hub for the generation and regulation of the negative resting membrane potential and neuronal excitability. K2P channels also play a central role in the response of cells to extracellular and intracellular signals as diverse as GPCR signaling, pH, and membrane stretch. TREK1 gene invalidation renders mice resistant to depression and TREK1 is inhibited by therapeutic doses of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) suggesting TREK1 as a candidate target for antidepressant medications. Together these properties of TREK1 suggest it as an attractive pharmacological target for the development of new antidepressant drugs and provide motivation for a deeper understanding of this channel’s function. In the past 6 years, we have contributed to greater understanding of these regulatory processes. We showed that TREK1 is regulated by associated proteins which can modify its biophysical properties. We determined the molecular basis of pH sensing in two of the channels and contributed to the elucidation of the mechanism of membrane trafficking and its regulation by GPCRs. In addition, we developed a novel optical imaging method to probe interactions of a channel’s C-terminal domain with the plasma membrane and showed that this interaction is involved in gating and regulation by GPCRs and the antidepressant fluoxetine. Most excitingly, we recently developed both light-gated versions of members of two K2P subfamilies and an important new method for optogenetics, which we call the photoswitched conditional subunit method, which makes it possible to endow native (unmodified) channels with sensitivity to light.

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