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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Scherbenske, M James
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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O'Neil, Roger G; Brown, Rachel C (2003) The vanilloid receptor family of calcium-permeable channels: molecular integrators of microenvironmental stimuli. News Physiol Sci 18:226-31
Liu, X; Zhang, M I N; Peterson, L B et al. (2003) Osmomechanical stress selectively regulates translocation of protein kinase C isoforms. FEBS Lett 538:101-6
Gao, Xiaochong; Wu, Ling; O'Neil, Roger G (2003) Temperature-modulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and -independent pathways. J Biol Chem 278:27129-37
Zhang, M I; O'Neil, R G (2001) Molecular characterization of rabbit renal epithelial calcium channel. Biochem Biophys Res Commun 280:435-9
Zhang, M I; O'Neil, R G (2001) Kinetics of activation of a PKC-regulated epithelial calcium channel. Cell Calcium 29:263-75
Thurman, C L; Burns, J S; O'Neil, R G (2000) Identifying the Ca(++) signalling sources activating chloride currents in Xenopus oocytes using ionomycin and thapsigargin. Cell Signal 12:629-35
Reid, J M; O'Neil, R G (2000) Osmomechanical regulation of membrane trafficking in polarized cells. Biochem Biophys Res Commun 271:429-34
Nutt, L K; O'Neil, R G (2000) Effect of elevated glucose on endothelin-induced store-operated and non-store-operated calcium influx in renal mesangial cells. J Am Soc Nephrol 11:1225-35
O'Neil, R G; Leng, L (1997) Osmo-mechanically sensitive phosphatidylinositol signaling regulates a Ca2+ influx channel in renal epithelial cells. Am J Physiol 273:F120-8
Zhang, M I; O'Neil, R G (1996) Regulated calcium channel in apical membranes renal proximal tubule cells. Am J Physiol 271:C1757-64

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