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A Mg2+nificient outlook on the channel-kinase TRPM6

Funder: Netherlands Organisation for Scientific Research (NWO)Project code: 863.13.010

A Mg2+nificient outlook on the channel-kinase TRPM6

Description

The present project investigates the unique channel-kinase TRPM6 (Transient Receptor Potential Melastatin 6) that belongs to the melastatin-related subfamily of TRP ion channels. TRPM6 has been identified as the magnesium (Mg2+) entry pathway in the distal convoluted tubule (DCT) of the kidney, where it functions as gatekeeper for controlling the bodys Mg2+ balance. The tight control of blood Mg2+ levels (0.7-1.1 mmol/L) is of central importance for various physiological processes and a low Mg2+ status (hypomagnesemia) has been found to be involved in the pathogenesis of diabetes mellitus type 2, osteoporosis, asthma, and heart and vascular diseases. TRPM6 is, together with its homologue TRPM7, the only known protein that combines a channel domain with an alpha-kinase domain. Kinases are key players in numerous cellular processes. They act as enzymes to phosphorylate target proteins and subsequently modulate their function. Importantly, the function of this carboxyl-terminally fused alpha-kinase domain is still poorly understood. The following key objectives will, therefore, be addressed: I) Phosphorylation-dependent regulation of TRPM6: phosphomapping by mass spectrometry will reveal phosphorylated residues in TRPM6 and their functional implications will be analyzed by electrophysiological and fluorescence microscopy methods. II) Identification of renal substrates of TRPM6: detect new kidney-specific proteins by mass spectrometry and study their effect on TRPM6 channel activity, kinase function and renal Mg2+ handling. III) Development and characterization of a cytosolic fluorescent Mg2+ probe: a new technically advanced fluorescent indicator for measuring intracellular Mg2+ concentrations ([Mg2+]i) will boost in-depth understanding of TRPM6 regulation. Taken together, research on the regulation of TRPM6 is still in its infancy. By using a complementary array of novel tools and state-of-the-art techniques, this project will disclose the molecular regulation of TRPM6 specifically involving Mg2+-dependent regulation, identification of renal substrates of the remarkable alpha-kinase and the functional implications of channel autophosphorylation.

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