: 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044455-11A1
Application #
6400947
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
1991-01-01
Project End
2006-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
11
Fiscal Year
2001
Total Cost
$339,750
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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