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J. Biol. Chem., Vol. 281, Issue 32, 23207-23217, August 11, 2006

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Nanomechanics of Hemichannel Conformations

CONNEXIN FLEXIBILITY UNDERLYING CHANNEL OPENING AND CLOSING^*

From the Neuroscience Research Institute, University of California, Santa Barbara, California 93106

Gap junctional hemichannels mediate cell-extracellular communication. A hemichannel is made of six connexin (Cx) subunits; each connexin has four transmembrane domains, two extracellular loops, and cytoplasmic amino- and carboxyl-terminals (CTs). The extracellular domains are arranged differently at non-junctional and junctional (gap junction) regions, although very little is known about their flexibility and conformational energetics. The cytoplasmic tail differs considerably in the size and amino acid sequence for different connexins and is predicted to be involved in the channel open and closed conformations. For large connexins, such as Cx43, the CT makes large cytoplasmic fuzz visible under electron microscopy. If this CT domain controls channel permeability by physical occlusion of the pore mouth, movement of this portion could open or close the channel. We used atomic force microscopy-based single molecule spectroscopy with antibody-modified atomic force microscopy tips and connexin mimetic peptide modified tips to examine the flexibility of extracellular loop and CT domains and to estimate the energetics of their movements. Antibody to the CT portion closer to the membrane stretches the tail to a shorter length, and the antibody to CT tail stretches the tail to a longer length. The stretch length and the energy required for stretching the various portions of the carboxyl tail support the ball and chain model for hemichannel conformational changes.

Received for publication, May 25, 2006 , and in revised form, June 9, 2006.

^* The work was supported by the National Institutes of Health and the Philip Morris External Research Program. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Neuroscience Research Institute, University of California, 5126 BioSci II Bldg., Santa Barbara, CA 93106. Tel.: 805-893-2350; Fax: 805-893-2005; E-mail: lal{at}lifesci.ucsb.edu.

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