Fondecyt Iniciación en Investigación Dr. Leandro Zúñiga

Fondecyt Iniciación en Investigación Proyecto N°11110217
Investigador Responsable: Dr. Leandro Zúñiga, Departamento de Fisiología

Roles of Lipid Rafts on Neuronal Two-pore Domain Potassium Channel Regulation

Ion channels are pores highly regulated which act controlling the ions flux across to cellular membranes. Among them, K_2P channels mediate the potassium leak or background current and in excitable cells this background current (I_KSO), has emerged as a critical point for the stabilization of membrane potential below the firing threshold. Controlling the cellular excitability and representing a primary and dynamic mechanism of control.

The tight regulation of K_2P channels is crucial for fine tuning of electrical properties of cells. Regarding that we previously identified keys amino acid residues for the gating in TALK and TASK potassium channels subfamilies (PNAS 2007 & PLoS ONE 2011), and recently the heterodimerization of TWIK-1 and TASK potassium subunits, conferring new regulation mechanism to these conformations (data unpublished).

And now, we are interested in a novel ion channels regulatory mechanism, involving lipid rafts, which has not been studied for K_2P. In this project, we present preliminary evidence for lipids mediated inhibition of background current in cerebellar granule neurons (CGN).

And, our research plan aims expanding the understanding of lipid rafts as physiologically relevant regulatory mechanism using molecular biology, biochemical and electrophysiological approaches. Lipids modulation will study in detail, including identification of potassium channels regulated, characterization of lipids environment effects, and also the domain involved in that regulation.

The studies will be done in HEK-293 cells (for the specific channels characterization) and cerebellar granule cells where K_2P channels are abundantly expressed.

The hypothesis of this project is that cholesterol-rich lipid rafts are a relevant regulatory mechanism for the activity of potassium channels in CGN and that mechanism is mediated, at least in part, through the K_2P channels.