BKca1CHANNEL REGULATION BY PKG IN VASCULAR SMOOTH MUSCLE

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Large-conductance Ca2+-activated K+ (BK[Ca]) channels play a critical role in the regulation ofl vascular tone, and they are thought to be important mediators of the vasodilatory effects of endothelial derived NO and exogenous vasodilators that activate the cGMP-dependent protein kinase (PKG). Here we propose to address questions that relate to the BK[Ca] channel's activation by PKG in vascular smooth muscle. In Aim 1 we will address questions having to do with the biochemical mechanism by which the BK[Ca] channel is activated by PKG. Does PKG stably associate with channel? Is a phosphatase required for PKG-mediated BK[Ca] -channel activation? Is the BK[Ca] channel's smooth muscle-specific beta1 subunit required? And does protein kinase C modulate the effect of PKG on the BK channel? In Aim 2 we will focus on the nature of PKG's effect, examining particularly its Ca2+ -dependence and its effect on the response of the channel to a Ca 2+ spark. And in Aim 3 we will examine whether PKGlalpha's leucine zipper domain is required for PKG-mediated modulation of Ca 2+ sparking and BK[Ca] channel opening in vivo. Results from the proposed work are expected to advance our understanding of the regulation of a key ion channel that regulates vasomotion, and they may suggest new strategies for the development of drugs to treat hypertension and ischemic cardiovascular diseases.