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J. Biol. Chem., Vol. 279, Issue 26, 26858-26867, June 25, 2004

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Roles of Molecular Regions in Determining Differences between Voltage Dependence of Activation of Ca_V3.1 and Ca_V1.2 Calcium Channels^*

Junying Li, Louisa Stevens, Norbert Klugbauer, and Dennis Wray

From the School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom and Institute of Experimental and Clinical Pharmacology and Toxicology, Albert Ludwigs University Freiburg, Freiburg D-79104, Germany

Voltage-dependent calcium channels are classified into low voltage-activated and high voltage-activated channels. We have investigated the molecular basis for this difference in voltage dependence of activation by constructing chimeras between a low voltage-activated channel (Ca_V3.1) and a high voltage-activated channel (Ca_V1.2), focusing on steady-state activation properties. Wild type and chimeras were expressed in oocytes, and two-electrode voltage clamp recordings were made of calcium channel currents. Replacement of domains I, III, or IV of the Ca 3.1 channel with the corresponding domain of Ca_V1.2 led ^Vto high voltage-activated channels; for these constructs the current/voltage (I/V) curves were similar to those for Ca_V1.2 wild type. However, replacement of domain II gave only a small shift to the right of the I/V curve and modulation of the activation kinetics but did not lead to a high voltage-activating channel with an I/V curve like Ca 1.2. We also investigated the role of the voltage sensor ^VS4 by replacing the S4 segment of Ca_V3.1 with that of Ca 1.2. For domain I, there was no shift in the I/V curve ^Vas compared with Ca_V3.1, and there were relatively small shifts to the right for domains III and IV. Taken together, these results suggest that domains I, III, and IV (rather than domain II) are apparently critical for channel opening and, therefore, contribute strongly to the difference in voltage dependence of activation between Ca 3.1 and Ca_V1.2. However, the S4 segments in domains I, ^VIII, and IV did not account for this difference in voltage dependence.

Received for publication, December 22, 2003 , and in revised form, April 19, 2004.

^* This work was supported in full by Biotechnology and Biological Sciences Research Council, Swindon, United Kingdom. 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.: 44-113-3434320; Fax: 44-113-3434228; E-mail: d.wray{at}leeds.ac.uk.

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