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J. Biol. Chem., Vol. 279, Issue 37, 38544-38554, September 10, 2004

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Biochemical Requirements for Inhibition of Connexin26-containing Channels by Natural and Synthetic Taurine Analogs^*

Liang Tao and Andrew L. Harris

From the Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Previous work has shown that protonated taurine and aminosulfonate pH buffers, including HEPES, can directly and reversibly inhibit connexin channels that contain connexin26 (Cx26) (Bevans, C. G., and Harris, A. L. (1999) J. Biol. Chem. 274, 3711–3719). The structural requirements for this inhibition were explored by studies of the effects of structural analogs of taurine on the activity of Cx26-containing reconstituted hemichannels from native tissue. Several analogs inhibited the channels, with a range of relative affinities and efficacies. Each active compound contains a protonated amine separated from an ionized sulfonate or sulfinate moiety by several methylene groups. The inhibition is eliminated if the sulfonate/sulfinate moiety or the amine is not present. Compounds that contain a protonated amine but lack a sulfonate/sulfinate moiety do not inhibit but do competitively block the effect of the active compounds. Compounds that lack the protonated amine do not significantly inhibit or antagonize inhibition. The results suggest involvement of the protonated amine in binding and of the ionized sulfur-containing moiety in effecting the inhibition. The maximal effect of the inhibitory compounds is enhanced when a carboxyl group is linked to the -carbon. Inhibition but not binding is stereospecific, with L-isomers being inhibitory and the corresponding D-isomers being inactive but able to antagonize inhibition by the L-isomers. Whereas not all connexins are sensitive to aminosulfonates, the well defined structural requirements described here argue strongly for a highly specific regulatory interaction with some connexins. The finding that cytoplasmic aminosulfonates inhibit connexin channels whereas other cytoplasmic compounds antagonize the inhibition suggests that gap junction channels are regulated by a complex interplay of cytoplasmic ligands.

Received for publication, May 20, 2004 , and in revised form, June 25, 2004.

^* This work was supported by National Institutes of Health Grants GM36044 and GM61406 (to A. L. H.). 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 Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, MSB I-643, 185 S. Orange Ave., Newark, NJ 07103. Tel.: 973-972-1620; Fax: 973-972-4554; E-mail: aharris{at}umdnj.edu.

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