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J. Biol. Chem., Vol. 280, Issue 1, 458-468, January 7, 2005

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Determination of the Functional Unit of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel

ONE POLYPEPTIDE FORMS ONE PORE^*

Zhi-Ren Zhang, Guiying Cui, Xuehong Liu, Binlin Song, David C. Dawson, and Nael A. McCarty, An Established Investigator of the American Heart Association¶

From the School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332-0230 and the Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239

The magnitudes and distributions of subconductance states were studied in chloride channels formed by the wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and in CFTRs bearing amino acid substitutions in transmembrane segment 6. Within an open burst, it was possible to distinguish three distinct conductance states referred to as the full conductance, subconductance 1, and subconductance 2 states. Amino acid substitutions in transmembrane segment 6 altered the duration and probability of occurrence of these subconductance states but did not greatly alter their relative amplitudes. Results from real time measurements indicated that covalent modification of single R334C-CFTR channels by [2-(trimethylammonium)ethyl]methanethiosulfonate resulted in the simultaneous modification of all three conductance levels in what appeared to be a single step, without changing the proportion of time spent in each state. This behavior suggests that at least a portion of the conduction path is common to all three conducting states. The time course for the modification of R334C-CFTR, measured in outside-out macropatches using a rapid perfusion system, was also consistent with a single modification step as if each pore contained only a single copy of the cysteine at position 334. These results are consistent with a model for the CFTR conduction pathway in which a single anion-conducting pore is formed by a single CFTR polypeptide.

Received for publication, August 23, 2004 , and in revised form, October 18, 2004.

^* This work was supported by NIDDK, National Institutes of Health, Grants DK056481 (to N. A. M.) and DK045880 (to D. C. D.), Cystic Fibrosis Foundation Grants MCCART00P0 (to N. A. M.) and DAWSON0210 (to D. C. D.), and American Heart Association Grant 0140174N. 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. Tel.: 404-385-2955; Fax: 404-894-0519; E-mail: Nael.McCarty{at}biology.gatech.edu.

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