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(Circulation Research. 2005;97:1270.)
© 2005 American Heart Association, Inc.

Cellular Biology

TRPV4 Forms a Novel Ca²⁺ Signaling Complex With Ryanodine Receptors and BK_Ca Channels

Scott Earley, Thomas J. Heppner, Mark T. Nelson, Joseph E. Brayden

From the Department of Pharmacology, University of Vermont College of Medicine, Burlington.

Correspondence to Scott Earley, PhD, Department of Pharmacology, University of Vermont College of Medicine, 89 Beaumont Ave, Burlington, VT 05405. E-mail Scott.Earley{at}uvm.edu

Vasodilatory factors produced by the endothelium are critical for the maintenance of normal blood pressure and flow. We hypothesized that endothelial signals are transduced to underlying vascular smooth muscle by vanilloid transient receptor potential (TRPV) channels. TRPV4 message was detected in RNA from cerebral artery smooth muscle cells. In patch-clamp experiments using freshly isolated cerebral myocytes, outwardly rectifying whole-cell currents with properties consistent with those of expressed TRPV4 channels were evoked by the TRPV4 agonist 4-phorbol 12,13-didecanoate (4-PDD) (5 µmol/L) and the endothelium-derived arachidonic acid metabolite 11,12 epoxyeicosatrienoic acid (11,12 EET) (300 nmol/L). Using high-speed laser-scanning confocal microscopy, we found that 11,12 EET increased the frequency of unitary Ca²⁺ release events (Ca²⁺ sparks) via ryanodine receptors located on the sarcoplasmic reticulum of cerebral artery smooth muscle cells. EET-induced Ca²⁺ sparks activated nearby sarcolemmal large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, measured as an increase in the frequency of transient K⁺ currents (referred to as "spontaneous transient outward currents" [STOCs]). 11,12 EET–induced increases in Ca²⁺ spark and STOC frequency were inhibited by lowering external Ca²⁺ from 2 mmol/L to 10 µmol/L but not by voltage-dependent Ca²⁺ channel inhibitors, suggesting that these responses require extracellular Ca²⁺ influx via channels other than voltage-dependent Ca²⁺ channels. Antisense-mediated suppression of TRPV4 expression in intact cerebral arteries prevented 11,12 EET–induced smooth muscle hyperpolarization and vasodilation. Thus, we conclude that TRPV4 forms a novel Ca²⁺ signaling complex with ryanodine receptors and BK_Ca channels that elicits smooth muscle hyperpolarization and arterial dilation via Ca²⁺-induced Ca²⁺ release in response to an endothelial-derived factor.

Key Words: Ca²⁺ sparks • Ca²⁺ transients • eicosanoids • ion channels • ryanodine receptor • vascular smooth muscle • vasodilation

Related Article:

EDHF Redux: EETs, TRPV4, and Ca²⁺ Sparks

Michael I. Kotlikoff
Circ. Res. 2005 97: 1209-1210. [Extract] [Full Text] [PDF]

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