HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/C231    most recent 00175.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Blum, A. E. Articles by Dubyak, G. R. Search for Related Content PubMed PubMed Citation Articles by Blum, A. E. Articles by Dubyak, G. R.

RECEPTORS AND SIGNAL TRANSDUCTION

Rho-family GTPases modulate Ca²⁺-dependent ATP release from astrocytes

Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio

Submitted 27 March 2008 ; accepted in final form 20 May 2008

Previously, we reported that activation of G protein-coupled receptors (GPCR) in 1321N1 human astrocytoma cells elicits a rapid release of ATP that is partially dependent on a G_q/phophospholipase C (PLC)/Ca²⁺ mobilization signaling cascade. In this study we assessed the role of Rho-family GTPase signaling as an additional pathway for the regulation of ATP release in response to activation of protease-activated receptor-1 (PAR1), lysophosphatidic acid receptor (LPAR), and M3-muscarinic (M3R) GPCRs. Thrombin (or other PAR1 peptide agonists), LPA, and carbachol triggered quantitatively similar Ca²⁺ mobilization responses, but only thrombin and LPA caused rapid accumulation of active GTP-bound Rho. The ability to elicit Rho activation correlated with the markedly higher efficacy of thrombin and LPA, relative to carbachol, as ATP secretagogues. Clostridium difficile toxin B and Clostridium botulinum C3 exoenzyme, which inhibit Rho-GTPases, attenuated the thrombin- and LPA-stimulated ATP release but did not decrease carbachol-stimulated release. Thus the ability of certain G_q-coupled receptors to additionally stimulate Rho-GTPases acts to strongly potentiate a Ca²⁺-activated ATP release pathway. However, pharmacological inhibition of Rho kinase I/II or myosin light chain kinase did not attenuate ATP release. PAR1-induced ATP release was also reduced twofold by brefeldin treatment suggesting the possible mobilization of Golgi-derived, ATP-containing secretory vesicles. ATP release was also markedly repressed by the gap junction channel inhibitor carbenoxolone in the absence of any obvious thrombin-induced change in membrane permeability indicative of hemichannel gating.

Rho GTPase; astrocyte; hemichannel

This article has been cited by other articles:

				H. N. Woodward, A. Anwar, S. Riddle, L. Taraseviciene-Stewart, M. Fragoso, K. R. Stenmark, and E. V. Gerasimovskaya PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L954 - L964. [Abstract] [Full Text] [PDF]

				L. Seminario-Vidal, S. Kreda, L. Jones, W. O'Neal, J. Trejo, R. C. Boucher, and E. R. Lazarowski Thrombin Promotes Release of ATP from Lung Epithelial Cells through Coordinated Activation of Rho- and Ca2+-dependent Signaling Pathways J. Biol. Chem., July 31, 2009; 284(31): 20638 - 20648. [Abstract] [Full Text] [PDF]

				D. A. Prosdocimo, D. C. Douglas, A. M. Romani, W. C. O'Neill, and G. R. Dubyak Autocrine ATP release coupled to extracellular pyrophosphate accumulation in vascular smooth muscle cells Am J Physiol Cell Physiol, April 1, 2009; 296(4): C828 - C839. [Abstract] [Full Text] [PDF]