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J. Biol. Chem., Vol. 282, Issue 48, 34801-34808, November 30, 2007

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Microtubule Motors Regulate I_SOC Activation Necessary to Increase Endothelial Cell Permeability^*

Songwei Wu¹, Hairu Chen, Mikhail F. Alexeyev^¶, Judy A. C. King^||, Timothy M. Moore^**, Troy Stevens, and Ronald D. Balczon^¶2

From the Departments of Molecular and Cellular Pharmacology, ^¶Cell Biology and Neuroscience, ^||Pathology, and ^**Medicine and the Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama 36688

Calcium store depletion activates multiple ion channels, including calcium-selective and nonselective channels. Endothelial cells express TRPC1 and TRPC4 proteins that contribute to a calcium-selective store-operated current, I_SOC. Whereas thapsigargin activates the I_SOC in pulmonary artery endothelial cells (PAECs), it does not activate I_SOC in pulmonary microvascular endothelial cells (PMVECs), despite inducing a significant rise in global cytosolic calcium. Endoplasmic reticulum exhibits retrograde distribution in PMVECs when compared with PAECs. We therefore sought to determine whether endoplasmic reticulum-to-plasma membrane coupling represents an important determinant of I_SOC activation in PAECs and PMVECs. Endoplasmic reticulum organization is controlled by microtubules, because nocodozole induced microtubule disassembly and caused retrograde endoplasmic reticulum collapse in PMVECs. In PMVECs, rolipram treatment produced anterograde endoplasmic reticulum distribution and revealed a thapsigargin-activated I_SOC that was abolished by nocodozole and taxol. Microtubule motors control organelle distribution along microtubule tracks, with the dynein motor causing retrograde movement and the kinesin motor causing anterograde movement. Dynamitin expression reduces dynein motor function inducing anterograde endoplasmic reticulum transport, which allows for direct activation of I_SOC by thapsigargin in PMVECs. In contrast, expression of dominant negative kinesin light chain reduces kinesin motor function and induces retrograde endoplasmic reticulum transport; dominant negative kinesin light chain expression prevented the direct activation of I_SOC by thapsigargin in PAECs. I_SOC activation is an important step leading to disruption of cell-cell adhesion and increased macromolecular permeability. Thus, microtubule motor function plays an essential role in activating cytosolic calcium transitions through the membrane I_SOC channel leading to endothelial barrier disruption.

Received for publication, June 1, 2007 , and in revised form, October 2, 2007.

^* This work was supported by National Institutes of Health Grants HL-60024 (to T. S.) and HL-66299 (to T. S., S. W., R. B., and M. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movies.

¹ To whom correspondence may be addressed: 307 N. University Blvd., MSB 3332, Mobile, AL 36688-0002. Tel.: 251-460-6366; Fax: 251-460-6798; E-mail: swu{at}jaguar1.usouthal.edu. ² To whom correspondence may be addressed: 307 N. University Blvd., MSB 2265, Mobile, AL 36688-0002. Tel.: 251-460-6776; Fax: 251-460-6771; E-mail: rbalczon{at}usouthal.edu.

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