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J. Biol. Chem., Vol. 281, Issue 8, 4823-4830, February 24, 2006

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A Molecular Determinant of Nickel Inhibition in Ca_v3.2 T-type Calcium Channels^*

Ho-Won Kang¹, Jin-Yong Park, Seong-Woo Jeong, Jin-Ah Kim^¶, Hyung-Jo Moon, Edward Perez-Reyes^||, and Jung-Ha Lee^¶2

From the Department of Life Science, ^¶Interdisciplinary Program of Biotechnology, Sogang University, Shinsu-dong, Seoul 121-742, Korea, the Department of Physiology, Institute of Basic Medical Science, Yonsei University Wonju College of Medicine, Ilsan-Dong 162, Wonju, Kangwon-Do, Korea, and the ^||Department of Pharmacology, University of Virginia, Charlottesville, Virginia, 22908

Molecular cloning studies have revealed that heterogeneity of T-type Ca²⁺ currents in native tissues arises from the three isoforms of Ca_v3 channels: Ca_v3.1, Ca_v3.2, and Ca_v3.3. From pharmacological analysis of the recombinant T-type channels, low concentrations (<50 µM) of nickel were found to selectively block the Ca_v3.2 over the other isoforms. To date, however, the structural element(s) responsible for the nickel block on the Ca_v3.2 T-type Ca²⁺ channel remain unknown. Thus, we constructed chimeric channels between the nickel-sensitive Ca_v3.2 and the nickel-insensitive Ca_v3.1 to localize the region interacting with nickel. Systematic assaying of serial chimeras suggests that the region preceding domain I S4 of Ca_v3.2 contributes to nickel block. Point mutations of potential nickel-interacting sites revealed that H191Q in the S3–S4 loop of domain I significantly attenuated the nickel block of Ca_v3.2, mimicking the nickel-insensitive blocking potency of Ca_v3.1. These findings indicate that His-191 in the S3–S4 loop is a critical residue conferring nickel block to Ca_v3.2 and reveal a novel role for the S3–S4 loop to control ion permeation through T-type Ca²⁺ channels.

Received for publication, September 16, 2005 , and in revised form, December 22, 2005.

^* This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2005-015-C00403), a grant from Sogang University (to J.-H. L.), and National Institutes of Health Grant NS038691 (to E. P.-R.). 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 Recipient of Seoul Science Fellowship.

² To whom correspondence should be addressed: Dept. of Life Science, Sogang University, Shinsu-Dong 1, Mapo-Gu, Seoul 121-742, Korea. Tel.: 82-2-705-8791; Fax: 82-2-704-3601; E-mail: jhleem{at}sogang.ac.kr.

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