The importance of mechanical sensing and transduction in sensory cells has long been known. In recent years it has become evident that mechanical stresses (osmo-mechanical stress from cell swelling, membrane stretch, shear stress) in non-sensory cells can play a major role in regulating numerous cell processes including calcium influx and, hence, Ca+ signaling. In kidney cells, mechanical stresses generated by physiological and pathophysiological states are known to activate Ca+ influx through purported Ca+ channels as the influx can be abolished by calcium channel blockers (e.g. Dihydropyridines (DHP), L-type Ca+ channel blocker). Recently they identified a novel DHP-sensitive Ca+ channel (Ca+-selective) on the apical border of rabbit proximal tubule cells that appears to play a central role in mechanically-induced states of Ca+ signaling. The channel is activated by cell swelling and membrane stretch. It appears to be regulated indirectly via mechano-sensitive regulation of phosphatidyl inositol hydrolysis (phospholipase C-b) andactivation of protein kinase C similar to that recently identified for L-type Ca+ channels in cardiac myocytes. The overall goal of the project is to characterize the function, regulation and structure of this novel channel with the following four Specific Aims: 1) To determine the role of the DHP-sensitive Ca+ channel in regulating intracellular calcium levels and Ca+ signaling during mechanically-stressed states (osmo-mechanical, membrane stretch); 2) To characterize the channel properties (single channel and whole cell currents) of the DHP-sensitive Ca+ channel and the effect of mechanical stresses on these properties; 3) To characterize the mechano-transduction pathway(s) regulating the DHP-sensitive Ca+ channel; and 4) To determine the molecular identity of the DHP-sensitive Ca+ channel in proximal tubule cells. The project will have broad implications to the role of mechanical stress in controlling numerous Ca-dependent functions in health and disease.
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