Voltage-dependent inactivation in a cardiac-skeletal chimeric calcium channel
FEBS Letters(1995)
Abstract
The loci for inactivation in calcium channel proteins are unknown. Mechanisms for inactivation may be distributed across Ca2+ channel subunits and appear to be complex, multiple and interacting. We took advantage of the properties of chimeras, constructed between cardiac (H4) and skeletal muscle (Sk4) calcium channel α1 subunits to study the molecular mechanism of inactivation in L-type calcium channels. Sk1H3, a chimeric construct of these two L-type calcium channels, was expressed in Xenopus oocytes in the absence of auxiliary subunits. Sk1H3 incorporated repeat I from skeletal muscle α1, and repeats II, III, IV from heart α1, subunit. Sk1H3 inactivated faster (τ ≈ 300 ms) and more fully than the wild-type H4 with Ba2+ ions as the charge carrier. Thus, inactivation of Sk1H3 was 90% complete after a 5-s conditioning pulse at +20 mV while inactivation of H4 was only 37% complete. Sk1H3 inactivation also developed at more negative potentials with E0.5 = −15 mV as compared to E0.5 = −5 mV for H4. In the presence of external calcium ions, the extent of inactivation significantly increased from 37 to 83% for H4 while inactivation of Sk1H3 was only slightly increased. Inactivation with Ba2+ as the charge carrier was confirmed at the single- channel level where averaged single-channel ensembles showed a similar rate of inactivation. Collectively, these observations demonstrate that Sk1H3 inactivation appears to have a prominent voltage-dependent component. Whether Sk1H3 inactivation involves interactions within repeat I alone or interactions between repeat I and site(s) located in the three other repeats of the α1 subunit has yet to be determined.
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Key words
Calcium channel,Inactivation,Chimera,Heart,Skeletal muscle,Mutagenesis
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