: Intracellular calcium ([Ca 2+]i) regulates excitability, contractility and the expression of genes in smooth muscle. Three different Ca2+signaling modalities (Ca2+ sparks, waves and global Ca2+) have been identified in smooth muscle, each with different frequency, amplitude and spatial components that encodes different functional outcomes. The discovery of Ca + sparks in smooth muscle has led to a paradigm shift, whereby one local Ca2+ signal sparks-can oppose the elevation in another-global Ca2+-through activation of large conductance, Ca2+-sensitive potassium (BK) channels. Little is known about the roles and regulation of Ca + waves in smooth muscle, although vasoconstrictors can increase their frequency. We have recently discovered that alkalization, which causes cerebral artery constriction, shifts Ca2+ signaling modalities from sparks to waves, and that the B1-subunit of the BK channel tunes the Ca2+-sensitivity of BK channels so as to translate Ca2+ signals to changes in arterial tone. Virtually nothing is known about Ca2+ signaling to transcription factors in native smooth muscle, despite the central role of Ca2+ in smooth muscle physiology and pathophysiology. This competitive renewal seeks to define the properties and roles of Ca2+ signals in cerebral artery smooth muscle.
In Specific Aim 1, the mechanisms by which three distinctly different stimuli, caffeine, pH and vasoconstrictors, activate Ca2+ waves will be elucidated, including the contribution of ryanodine receptors and 1P3 receptors to the induction of waves. We will explore the exciting possibility that Ca2+ waves have central roles in regulating excitability through BK channels (Aim 2) and transcription factors (Aim 3).
Specific Aim 2 will explore the functional coupling of Ca2+ sparks and waves to BK channels, by exploring the novel concepts that the membrane potential, cGMP-dependent protein kinase (PKG), and the B1-subunit of the BK channel determine the coupling of Ca2+ sparks and waves to BK channels, and that this coupling varies across the cell surface.
Aims 1 and 2 will serve as the foundation for the study of communication, direct and indirect, between Ca2+ signaling modalities and transcription factors (CREB and NFAT) in intact cerebral arteries (Aim 3). This work should provide the first integrated view of Ca2+ signaling and excitability, contractility and transcription factors in cerebral arteries, and as such significantly enhance our understanding of arterial function in health and disease.
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