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J. Biol. Chem., Vol. 281, Issue 30, 20920-20931, July 28, 2006

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Enhanced Neurite Outgrowth in PC12 Cells Mediated by Connexin Hemichannels and ATP^*

Daniel J. Belliveau, Mahmud Bani-Yaghoub, Becky McGirr, Christian C. G. Naus^¶, and Walter J. Rushlow^||1

From the Departments of ^||Psychiatry and Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5A5, the ^¶Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, and the Neurogenesis & Brain Repair Group, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada

Gap junctions have traditionally been described as transmembrane channels that facilitate intercellular communication via the passage of small molecules. Connexins, the basic building blocks of gap junctions, are expressed in most mammalian tissues including the developing and adult central nervous system. During brain development, connexins are temporally and spatially regulated suggesting they play an important role in the proper formation of the central nervous system. In the current study, connexins 32 and 43 were overexpressed in PC12 cells to determine whether connexins are involved in neuronal differentiation. Both connexin 32 and 43 were appropriately trafficked to the cell membrane following overexpression and resulted in the formation of functional gap junctions. Connexin overexpression was found to cause enhanced neurite outgrowth in PC12 cells treated with nerve growth factor to initiate neuritogenesis. Surprisingly, however, enhanced neurite outgrowth was found to be the consequence of functional hemichannel formation as opposed to traditional intercellular communication. Additional analysis revealed that ATP was released into the media likely through hemichannels and acted on purinergic receptors to cause enhanced neurite outgrowth. Collectively, the results of the current study suggest that connexins may play an important role in neuronal differentiation by non-traditional mechanisms.

Received for publication, January 3, 2006 , and in revised form, May 26, 2006.

^* This work was supported by grants from the Canadian Institutes of Health Research (to C. C. G. N.), Ontario Mental Health Foundation (to W. J. R.), and the Natural Sciences and Engineering Research Council (to W. J. R. and D. J. B.). 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.

¹ To whom correspondence should be addressed: Dept. of Psychiatry, London Health Sciences Centre, University Campus, Rm. B9-144, 339 Windermere Rd., London, Ontario N6A 5A5, Canada. Tel.: 519-685-8500 (ext. 34935); Fax: 519-663-3935; E-mail: wrushlow{at}uwo.ca.

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