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J. Biol. Chem., Vol. 278, Issue 46, 45528-45538, November 14, 2003

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Methanethiosulfonate Ethylammonium Block of Amine Currents through the Ryanodine Receptor Reveals Single Pore Architecture^*

Georgia I. Anyatonwu, Edmond D. Buck¶, and Barbara E. Ehrlich||

From the Departments of Pharmacology and Molecular & Cellular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8356 and ^¶Warner Instruments, Inc., Hamden, Connecticut 06514

The homotetrameric structure of the ryanodine-sensitive intracellular calcium (Ca²⁺) release channel (ryanodine receptor (RyR)) suggests that the four RyR subunits either combine to form a single pore or that each RyR subunit is an independently conducting pathway. Previously we showed that methanethiosulfonate ethylammonium (MTSEA⁺) covalently modifies the RyR to reduce current amplitudes in a time-dependent and stepwise manner. To ascertain the number of functionally conducting pores in the RyR, two approaches were combined: modification of the receptor by MTSEA⁺ and the use of different sized current carriers. Previous reports (Tinker, A., and Williams, A. J. (1993) J. Gen. Physiol. 102, 1107–1129) have shown that the organic cations methylamine, dimethylamine, ethylamine, and trimethylamine are permeant through the RyR but with reduced current amplitude depending upon the diameter of the respective amine. Experiments using the thiol reagent MTSEA⁺ to modify the channel protein showed that the current amplitudes decrease in steps leading to complete block of the channel when cesium (Cs⁺) is the current carrier. MTSEA⁺ modification decreased the number of channel substates as the diameter of the current carrier increased. Comparison of the degree of inhibition of MTSEA⁺-modified currents allows for differentiation between the two models for channel architecture. These results demonstrate that the conduction pathway for the RyR is comprised of a single central pore.

Received for publication, July 21, 2003 , and in revised form, August 29, 2003.

^* This work was supported in part by National Institutes of Health grants and a grant-in-aid from the Connecticut Heart Association. 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.

Supported in part by a pharmacology training grant.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, Yale University, 333 Cedar St., New Haven, CT 06520-8356. Tel.: 203-737-1188; Fax: 203-737-2027; E-mail: barbara.ehrlich{at}yale.edu.

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