KINASE REGULATION OF L TYPE CALCIUM CHANNELS

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Ion channels play a central role as modulators of vascular smooth muscle contractile activity. Of particular relevance in this regard are voltage gated L-type Ca channels (Ca(L)) which control calcium entry into the cell. The activity of Ca(L) channels can be modulated by various kinase cascades that lead either to direct phosphorylation of the channel or phospharylation of some upstream intermediary. In particular, there is convincing evidence that the cAMP/PKA pathway, the cGMP/PKG pathway and the PL/PKC pathway play important roles as modulators of Ca(L) channels. However, the details of how these pathways modulate channel activity are still not clear. The present study investigates kinase regulation of Ca(L) channels in smooth muscle cells of the rabbit portal vein. Experiments are described to investigate the role of G-protein subunits, anchoring proteins, phosphodiesterase activity and phosphatase activity as mediators/modulators of the PKA, PKG and PKC pathways. Whole cell and isolated patch recordings will be undertaken on native vascular myocytes and on Ca(L) channels expressed in mammalian HEK293 cells. The overall hypothesis for these studies is that kinase regulation of Ca(L) channels represents a summation of multiple divergent actions which are set in motion when agonist binds to a receptor. By understanding in greater detail the mechanisms which control calcium entry into vascular smooth muscle cells we may aid in the development of drugs which more selectively modulate vascular Ca(L) channels activity and hence vascular tone. Controlling vascular tone is of central importance in the management of vascular diseases such as high blood pressure and vasospasm which can lead to ischemia, stroke, infarction and ultimately death.