The function of cerebral arteries is to provide an adequate supply of blood to the brain. TO achieve this function cerebral arteries must alter their diameter in response to physiological stimuli. Arterial diameter is regulated by the contractile state of vascular smooth muscle cells (VSMCs), which is regulated by the activity of voltage-dependent Ca2+ channels (VDCCs). The current view is that VDCCs constrict cerebral arteries through a direct contribution of Ca2+ or indirectly, by activating Ca2+ release through ryanodine receptors (RYRs) in the sarcoplasmic reticulum RyRs, called """"""""Ca2+ sparks"""""""", hyperpolarize VSMCs by activating nearby Ca2+-sensitive potassium (K/ca) channels which close VDCCs, reduces cellular Ca2+ and thus dilates cerebral arteries. This findings underscore the importance of the location, frequency and amplitude of local Ca2+ signals in the function of VSMCs. Recent work by the PI and the collaborator suggest that vasodilators like forskolin and nitric oxide (NO) acting, respectively, through protein kinase A and G alter in a fundamental and previously unsuspected way the communication between VDCCs and RyRs. The goal of this collaborative proposal is to test the hypothesis that activation of protein kinase A and G relax cerebral arteries because they enable local Ca2+ signals from VDCCs to activate K/Ca channels and test this hypothesis the PI and collaborator will perform a series of complementary experiments that involve the use of electrophysiological, confocal microscopy and molecular techniques available in their laboratories. This proposal has three specific aims. 1). To understand the communication between VDCC and RyR, and its modulation by PKA. 2) To understand the communication between VDCC and RyR, and its modulation by PKG. 3). To understand the role of the SR protein phospholamban in the regulation of the communication between VDCCs and RyRs. While the PI will focus on the portions of the proposal involving dissociated VSMCs and gene- transfer, the collaborator will focus on experiments involving intact cerebral arteries. This division of worth will allow the complementary expertise of both investigators ti be applied in a mutually beneficial way. The proposed work should provide new fundamental information on the mechanisms that regulate tone in cerebral arteries and provide insights in the treatment of clinical conditions such as hypertension, stroke, cerebral vasospasm and migraine.
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