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J. Biol. Chem., Vol. 282, Issue 12, 8895-8904, March 23, 2007

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Aminosulfonate Modulated pH-induced Conformational Changes in Connexin26 Hemichannels^*

Jinshu Yu¹, Christian A. Bippes¹, Galen M. Hand, Daniel J. Muller, and Gina E. Sosinsky²

From the BioTechnological Center, University of Technology Dresden, Tatzberg 47-51, 01307 Dresden, Germany and the Department of Neurosciences, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California 92093

Gap junction channels regulate cell-cell communication by passing metabolites, ions, and signaling molecules. Gap junction channel closure in cells by acidification is well documented; however, it is unknown whether acidification affects connexins or modulating proteins or compounds that in turn act on connexins. Protonated aminosulfonates directly inhibit connexin channel activity in an isoform-specific manner as shown in previously published studies. High-resolution atomic force microscopy of force-dissected connexin26 gap junctions revealed that in HEPES buffer, the pore was closed at pH < 6.5 and opened reversibly by increasing the pH to 7.6. This pH effect was not observed in non-aminosulfonate buffers. Increasing the protonated HEPES concentration did not close the pore, indicating that a saturation of the binding sites occurs at 10 mM HEPES. Analysis of the extracellular surface topographs reveals that the pore diameter increases gradually with pH. The outer connexon diameter remains unchanged, and there is a 6.5° rotation in connexon lobes. These observations suggest that the underlying mechanism closing the pore is different from an observed Ca²⁺-induced closure.

Received for publication, October 2, 2006 , and in revised form, January 5, 2007.

^* This work was supported in part by the funding from the Deutsche Forschungsgemeinschaft (to D. J. M.), National Institutes of Health Grants GM065937 and GM072881, and National Science Foundation Grant MCB-0131425 (to G. E. S.). 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 movie M1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: University of California at San Diego, 1070 Basic Science Bldg. MC 0608, 9500 Gilman Dr., La Jolla, CA 92093-0608. Tel.: 858-534-0128; Fax: 858-534-7497; E-mail: gsosinsky{at}ucsd.edu.

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				A. Oshima, K. Tani, Y. Hiroaki, Y. Fujiyoshi, and G. E. Sosinsky Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule PNAS, June 12, 2007; 104(24): 10034 - 10039. [Abstract] [Full Text] [PDF]