Small (resistance-size) cerebral arteries and arterioles control regional brain blood flow, thereby providing neurons and other brain cells with necessary oxygen and nutrients. An essential regulator of artery contractility is smooth muscle cell membrane potential, which is controlled by ion channels. Hypertension is associated with increased risk for cerebral diseases, including stroke and dementia. Cerebral arteries from hypertensive subjects are depolarized, leading to elevated contractility, but mechanisms involved in this pathological alteration are unclear. Previous studies have focused on identifying mechanisms that regulate the activity of ion channels located in the plasma membrane of arterial smooth muscle cells. In contrast, mechanisms that control the number of functional ion channels and their auxiliary subunits in the plasma membrane of smooth muscle cells are unclear. Large-conductance calcium (Ca2+)-activated potassium (BKCa) channels are a major physiological modulator of arterial smooth muscle cell membrane potential and contractility. Arterial smooth muscle cells express two BKCa channel subunits: a pore-forming (BK) and an auxiliary 1 that is essential for channel physiological functions. This application stems from novel preliminary data indicating that physiological stimuli control BK and 1 surface expression to modulate channel subunit composition, channel activity and arterial contractility. We also provide evidence that hypertension is associated with pathological alterations in mechanisms that regulate BKCa channel subunit surface expression, thereby promoting vasoconstriction.
Three specific aims will be investigated to test the central hypothesis that vasoregulatory stimuli modulate surface expression of BKCa channel subunits to control cerebral artery contractility, and that pathological modification of these processes leads to vasoconstriction associated with cerebrovascular disease.
Aim 1 will examine the hypothesis that vasodilators and vasoconstrictors regulate 1 subunit surface expression to control BKCa channel activity in smooth muscle cells and arterial contractility.
Aim 2 will investigate the hypothesis that vasoconstrictors and vasodilators modulate BK surface expression and degradation to regulate smooth muscle cell BKCa channel activity and arterial contractility.
Aim 3 will explore the hypothesis that hypertension is associated with dysfunctional control of BK and 1 subunit surface expression that stimulates vasoconstriction. Methods used to test these hypotheses will include arterial biotinylation, FRET, RNAi, co-IP, immunofluorescence, patch-clamp electrophysiology, membrane potential recording, intracellular Ca2+ imaging and arterial myography. This proposal will provide significant novel information concerning cerebral artery contractility regulation by physiological and pathological mechanisms that control BKCa channel surface expression.

Public Health Relevance

Arterial smooth muscle cell plasma membrane ion channels control vascular contractility and regional organ blood flow, with pathological alterations in ion channel function contributing to cardiovascular diseases. Studies have investigated mechanisms that regulate the activity of plasma membrane-resident ion channels, but processes that control surface expression of these proteins in arterial myocytes are unclear. This proposal will investigate the novel hypotheses that physiological stimuli regulate surface expression of BKCa channel subunits to control vascular contractility and pathological alterations in mechanisms controlling BKCa channel surface expression contribute to cerebrovascular dysfunction in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067061-13
Application #
8842680
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Charette, Marc F
Project Start
2001-04-01
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
13
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
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Dopico, Alex M; Bukiya, Anna N; Jaggar, Jonathan H (2018) Calcium- and voltage-gated BK channels in vascular smooth muscle. Pflugers Arch 470:1271-1289
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Leo, M Dennis; Zhai, Xue; Yin, Wen et al. (2018) Impaired Trafficking of ?1 Subunits Inhibits BK Channels in Cerebral Arteries of Hypertensive Rats. Hypertension 72:765-775
Zhai, Xue; Leo, M Dennis; Jaggar, Jonathan H (2017) Endothelin-1 Stimulates Vasoconstriction Through Rab11A Serine 177 Phosphorylation. Circ Res 121:650-661
Leo, M Dennis; Zhai, Xue; Muralidharan, Padmapriya et al. (2017) Membrane depolarization activates BK channels through ROCK-mediated ?1 subunit surface trafficking to limit vasoconstriction. Sci Signal 10:
Hasan, Raquibul; Leeson-Payne, Alasdair T S; Jaggar, Jonathan H et al. (2017) Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 Channels. Sci Rep 7:45098
Leo, M Dennis; Jaggar, Jonathan H (2017) Trafficking of BK channel subunits controls arterial contractility. Oncotarget 8:106149-106150
Kidd, Michael W; Bulley, Simon; Jaggar, Jonathan H (2017) Angiotensin II reduces the surface abundance of KV 1.5 channels in arterial myocytes to stimulate vasoconstriction. J Physiol 595:1607-1618

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