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Control of Ion Conduction in L-type Ca²⁺ Channels by the Concerted Action of S5–6 Regions

Department of Pharmacology and Program in Neuroscience, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence: Address reprint requests to William A. Sather, Department of Pharmacology, Box B-138, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. Tel.: 303-315-3986; Fax: 303-315-2503; E-mail: william.sather{at}uchsc.edu.

Voltage-gated L-type Ca²⁺ channels from cardiac (_1C) and skeletal (_1S) muscle differ from one another in ion selectivity and permeation properties, including unitary conductance. In 110 mM Ba²⁺, unitary conductance of _1S is approximately half that of _1C. As a step toward understanding the mechanism of rapid ion flux through these highly selective ion channels, we used chimeras constructed between _1C and _1S to identify structural features responsible for the difference in conductance. Combined replacement of the four pore-lining P-loops in _1C with P-loops from _1S reduced unitary conductance to a value intermediate between those of the two parent channels. Combined replacement of four larger regions that include sequences flanking the P-loops (S5 and S6 segments along with the P-loop-containing linker between these segments (S5–6)) conferred _1S-like conductance on _1C. Likewise, substitution of the four S5–6 regions of _1C into _1S conferred _1C-like conductance on _1S. These results indicate that, comparing _1C with _1S, the differences in structure that are responsible for the difference in ion conduction are housed within the S5–6 regions. Moreover, the pattern of unitary conductance values obtained for chimeras in which a single P-loop or single S5–6 region was replaced suggest a concerted action of pore-lining regions in the control of ion conduction.

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