COBRE: UNR: ROLE OF INTEGRINS IN CHLORIDE CHANNEL REGULATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mechanisms that link cell swelling to activation of volume-sensitive outwardly rectifying chloride channels (VSOACs) remain unknown even though a number of intracellular signaling pathways have been implicated. The activation of these channels is believed to be involved in cell volume homeostasis since they may contribute to regulatory volume decreases (RVD) in response to cell swelling. It has been speculated that the actual stimulus for channel activation may involve mechanical stretch of the membrane, rather than cell volume changes per se, and thus these channels might be mechanosensitive. However, despite numerous attempts, direct evidence supporting the hypothesis that VSOACs may represent a new class of mechanosensitive anion channels has been lacking. Recently, two new studies have resurrected the mechanosensitive hypothesis by providing convincing evidence that VSOAC activation may be linked to mechanical stretch of integrin receptors located on the myocyte membrane (Browe & Baumgarten, J Gen Physiol 122: 689-702, 2003; & J Gen Physiol 124: 273-287, 2004). Using state of the art molecular and functional methods, as well as validated in vitro and in vivo models, this new COBRE project will specifically examine the role of integrins in the regulation of VSOACs in cardiac myocytes. Three specific aims will be sought: 1) Identify the integrin ? subunit(s) and exctracellular matrix proteins involved in the regulation of VSOACs in the heart; 2) Determine the role of the voltage-gated chloride channel ClC-3 as a candidate protein responsible for the native VSOAC activated by integrin receptor stimulation; and 3) Develop in vitro and in vivo models to dissect the molecular pathways involved in integrin-mediated VSOAC activation. It is anticipated that this project will unravel novel findings with respect to key signaling events involved in the activation of VSOACs by integrin-mediated stretch of the membrane which could play an important role in the functional changes and remodeling of the heart associated with hypertrophy and heart failure.