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Accession number;04A0196245
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| Title;Molecular and pharmacological bases for the gating regulation of L-type voltage-dependent Ca2+ channels. |
| Author;
AKAHANE SATOMI
(Univ. Tokyo, Graduate School of Parmaceutical Sciences, JPN)
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Journal Title;Folia Pharmacologica Japonica
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Journal Code:G0740A
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ISSN:0015-5691
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VOL.123;NO.3;PAGE.197-209(2004)
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| Figure&Table&Reference;FIG.4, TBL.1, REF.50 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;The voltage-dependent L-type Ca2+ channel plays a key role in the spacial and temporal regulation of Ca2+. In cardiac excitation-contraction coupling, Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs), triggered by Ca2+ entry through the nearby L-type Ca2+ channel, induces the Ca2+-dependent inactivation (CDI) of the Ca2+ channel. We demonstrated that the CICR-dependent CDI of L-type Ca2+ channels, under control of the privileged cross-signaling between L-type Ca2+ channels and RyRs, plays important roles for monitoring and tuning the SR Ca2+ content via changes of AP waveform and the amount of Ca2+-influx during AP in ventricular myocytes. L-type Ca2+ channels are modulated by the binding of Ca2+ channel antagonists and agonists to the pore-forming .ALPHA.1C subunit. We identified Phe1112 and Ser1115 in the pore-forming IIIS5-S6 linker region of the .ALPHA.1C subunit as critical determinants of the binding of dihydropyridines (DHP). Interestingly, double mutant Ca2+ channel (F1112A/S1115A) failed to discriminate between a DHP Ca2+ channel agonist and antagonist stereoisomers. We proposed that Phe1112 and Ser1115 in the pore-forming IIIS5-S6 linker region is required for the stabilization of the Ca2+ channel in the open state by Ca2+ channel agonists and further proposed a novel model for the DHP-binding pocket of the .ALPHA.1C subunit. These integrative studies on the gating regulation of cardiac L-type Ca2+ channels will provide the molecular basis for the pharmacology of Ca2+ channel modulators. (author abst.) |
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