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The Journal of Neuroscience, July 1, 2009, 29(26):8321-8328; doi:10.1523/JNEUROSCI.6191-08.2009

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Cellular/Molecular
Location of the β4 Transmembrane Helices in the BK Potassium Channel

Roland S. Wu,¹ Neelesh Chudasama,¹ Sergey I. Zakharov,¹ Darshan Doshi,¹ Howard Motoike,⁵ Guoxia Liu,¹ Yongneng Yao,³ Xiaowei Niu,^1,3 Shi-Xian Deng,² Donald W. Landry,² Arthur Karlin,³ and Steven O. Marx^1,4

Divisions of ¹Cardiology and ²Experimental Therapeutics, Department of Medicine, ³Center for Molecular Recognition, Departments of Biochemistry, Physiology, and Neurology, and ⁴Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and ⁵Department of Natural and Applied Sciences, LaGuardia Community College, Long Island City, New York 11101

Correspondence should be addressed to either of the following: Steven O. Marx, Department of Medicine, College of Physicians and Surgeons, 630 West 168th Street, Columbia University, New York, NY 10032, Email: sm460{at}columbia.edu; or Arthur Karlin, Center for Molecular Recognition, College of Physicians and Surgeons, 630 West 168th Street, Columbia University, New York, NY 10032, Email: ak12{at}columbia.edu

Large-conductance, voltage- and Ca²⁺-gated potassium (BK) channels control excitability in a number of cell types. BK channels are composed of subunits, which contain the voltage-sensor domains and the Ca²⁺- sensor domains and form the pore, and often one of four types of β subunits, which modulate the channel in a cell-specific manner. β4 is expressed in neurons throughout the brain. Deletion of β4 in mice causes temporal lobe epilepsy. Compared with channels composed of alone, channels composed of and β4 activate and deactivate more slowly. We inferred the locations of the two β4 transmembrane (TM) helices TM1 and TM2 relative to the seven TM helices, S0–S6, from the extent of disulfide bond formation between cysteines substituted in the extracellular flanks of these TM helices. We found that β4 TM2 is close to S0 and that β4 TM1 is close to both S1 and S2. At least at their extracellular ends, TM1 and TM2 are not close to S3–S6. In six of eight of the most highly crosslinked cysteine pairs, four crosslinks from TM2 to S0 and one each from TM1 to S1 and S2 had small effects on the V₅₀ and on the rates of activation and deactivation. That disulfide crosslinking caused only small functional perturbations is consistent with the proximity of the extracellular ends of TM2 to S0 and of TM1 to S1 and to S2, in both the open and closed states.

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Received Dec. 30, 2008; revised April 15, 2009; accepted April 25, 2009.

Correspondence should be addressed to either of the following: Steven O. Marx, Department of Medicine, College of Physicians and Surgeons, 630 West 168th Street, Columbia University, New York, NY 10032, Email: sm460{at}columbia.edu; or Arthur Karlin, Center for Molecular Recognition, College of Physicians and Surgeons, 630 West 168th Street, Columbia University, New York, NY 10032, Email: ak12{at}columbia.edu

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