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Differential Modulation of Cardiac Ca²⁺ Channel Gating by ß-Subunits

Igor Dzhura ^* and Alan Neely ^* 

^* Department of Physiology, Texas Tech University, Lubbock, Texas USA; and Centro de Neurosciencias de Valparaíso, University of Valparaíso, Valparaíso, Chile

Correspondence: Address reprint requests to Alan Neely, Centro de Neurociencias de Valparaíso, Universidad de Valparaíso, Gran Bretaña 1111, Valparaíso, Chile. Tel.: 56-32-50-8054; Fax: 56-32-28-3320; E-mail: alan.neely{at}uv.cl.

To investigate the mechanisms that increase ionic currents when Ca²⁺ channels' ₁ subunits are co-expressed with the ß-subunits, we compared channel activity of Ca_V1.2 (_1C) co-expressed with ß_1a and ß_2a in Xenopus oocytes. Normalized by charge movement, ionic currents were near threefold larger with ß_2a than with ß_1a. At the single-channel level, the open probability (P_o) was over threefold larger with ß_2a, and traces with high P_o were more frequent. Among traces with P_o > 0.1, the mean duration of burst of openings (MBD) were nearly twice as long for _1Cß_2a (15.1 ± 0.7 ms) than for _1Cß_1a (8.4 ± 0.5 ms). Contribution of endogenous ß_3xo was ruled out by comparing MBDs with _1C-cRNA alone (4.7 ± 0.1 ms) with ß_3xo (14.3 ± 1.1 ms), and with ß_1b (8.2 ± 0.5 ms). Open-channel current amplitude distributions were indistinguishable for _1Cß_1a and _1Cß_2a, indicating that opening and closing kinetics are similar with both subunits. Simulations with constant opening and closing rates reproduced the microscopic kinetics accurately, and therefore we conclude that the conformational change-limiting MBD is differentially regulated by the ß-subunits and contributes to the larger ionic currents associated with ß_2a, whereas closing and opening rates do not change, which should reflect the activity of a separate gate.

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