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J. Biol. Chem., Vol. 278, Issue 36, 34299-34308, September 5, 2003

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G Mediates the Interplay between Tubulin Dimers and Microtubules in the Modulation of G_q Signaling^*

Juliana S. Popova  and Mark M. Rasenick   ¶

From the Departments of Physiology and Biophysics and Psychiatry, College of Medicine, University of Illinois, Chicago, Illinois 60612-7342

Agonist stimulation causes tubulin association with the plasma membrane and activation of PLC1 through direct interaction with, and transactivation of, G_q. Here we demonstrate that G interaction with tubulin down-regulates this signaling pathway. Purified G, alone or with phosphatidylinositol 4,5-bisphosphate (PIP₂), inhibited carbachol-evoked membrane recruitment of tubulin and G_q transactivation by tubulin. Polymerization of microtubules elicited by G overrode tubulin translocation to the membrane in response to carbachol stimulation. G sequestration of tubulin reduced the inhibition of PLC1 observed at high tubulin concentration. G₁₂ interacted preferentially with tubulin-GDP, whereas G_q was transactivated by tubulin-GTP. Prenylation of the ₂ polypeptide was required for G/tubulin interaction. Both confocal microscopy and coimmunoprecipitation studies revealed the spatiotemporal pattern of G/tubulin interaction during carbachol stimulation of neuroblastoma SK-N-SH cells. In resting cells G localized predominantly at the cell membrane, whereas tubulin was found in well defined microtubules in the cytosol. Within 2 min of agonist exposure, a subset of tubulin translocated to the plasma membrane and colocalized with G. Fifteen min post-carbachol addition, tubulin and G colocalized in vesicle-like structures in the cytosol. G/tubulin colocalization increased after pretreatment of cells with the microtubule-depolymerizing agent, colchicine, and was inhibited by taxol. Taxol also inhibited carbachol-induced PIP₂ hydrolysis. It is suggested that G/tubulin interaction mediates internalization of membrane-associated tubulin at the offset of PLC1 signaling. Newly cytosolic G/tubulin complexes might promote microtubule polymerization attenuating further tubulin association with the plasma membrane. Thus G protein-coupled receptors might evoke G and G to orchestrate regulation of phospholipase signaling by tubulin dimers and control of cell shape by microtubules.

Received for publication, February 19, 2003 , and in revised form, May 5, 2003.

^* This work was supported by National Institutes of Health Grants MH 39595 and AG 15482 (to M. M. R.). 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 Physiology & Biophysics, University of Illinois at Chicago, 835 S. Wolcott Ave., m/c 901, Chicago, IL 60612-7342. Tel.: 312-996-6641; Fax: 312-996-1414; E-mail Raz{at}uic.edu.

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