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J. Biol. Chem., Vol. 279, Issue 13, 12959-12966, March 26, 2004

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Regulation of Ca²⁺-dependent K⁺ Current by _v3 Integrin Engagement in Vascular Endothelium^*

Junya Kawasaki, George E. Davis, and Michael J. Davis¶

From the Departments of Medical Physiology and Pathology and Laboratory Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Interactions between endothelial cells and extracellular matrix proteins are important determinants of endothelial cell signaling. Endothelial adhesion to fibronectin through _v3 integrins or the engagement and aggregation of luminal _v3 receptors by vitronectin triggers Ca²⁺ influx. However, the underlying signaling mechanisms are unknown. The electrophysiological basis of _v3 integrin-mediated changes in endothelial cell Ca²⁺ signaling was studied using whole cell patch clamp and microfluorimetry. The resting membrane potential of bovine pulmonary artery endothelial cells averaged -60 ± 3 mV. In the absence of intracellular Ca²⁺ buffering, the application of soluble vitronectin (200 µg/ml) resulted in activation of an outwardly rectifying K⁺ current at holding potentials from -50 to +50 mV. Neither a significant shift in reversal potential (in voltage clamp mode) nor a change in membrane potential (in current clamp mode) occurred in response to vitronectin. Vitronectin-activated current was significantly inhibited by pretreatment with the _v3 integrin antibody LM609 by exchanging extracellular K⁺ with Cs⁺ or by the application of iberiotoxin, a selective inhibitor of large-conductance, Ca²⁺-activated K⁺ channels. With intracellular Ca²⁺ buffered by EGTA in the recording pipette, vitronectin-activated K⁺ current was abolished. Fura-2 microfluorimetry revealed that vitronectin induced a significant and sustained increase in intracellular Ca²⁺ concentration, although vitronectin-induced Ca²⁺ current could not be detected. This is the first report to show that an endothelial cell ion channel is regulated by integrin activation, and this K⁺ current likely plays a crucial role in maintaining membrane potential and a Ca²⁺ driving force during engagement and activation of endothelial cell _v3 integrin.

Received for publication, December 17, 2003 , and in revised form, January 12, 2004.

^* This work was supported by National Institutes of Health Grants HL-60180 (to M. J. D.) and HL-59971 to (to G. E. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Medical Physiology, Rm. 346, Reynolds Medical Bldg., Texas A&M University College of Medicine, College Station, TX 77845. Tel.: 979-845-7819; Fax: 979-847-8635; E-mail: mjd{at}tamu.edu.

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