Calmodulin supports both inactivation and facilitation of L-type calcium channels

被引:703
|
作者
Zühlke, RD
Pitt, GS
Deisseroth, K
Tsien, RW
Reuter, H [1 ]
机构
[1] Univ Bern, Dept Pharmacol, CH-3010 Bern, Switzerland
[2] Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA
[3] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA
关键词
D O I
10.1038/20200
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac contraction(1), controls hormone secretion from endocrine cells(2) and initiates transcriptional events that support learning and memory(3). These channels are examples of molecular signal-transduction units that regulate themselves through their own activity. Among the many types of voltage-gated Ca2+ channel, L-type Ca2+ channels particularly display inactivation and facilitation, both of which are closely linked to the earlier entry of Ca2+ ions(4-10). Both forms of autoregulation have a significant impact on the amount of Ca2+ that enters the cell during repetitive activity, with major consequences downstream. Despite extensive biophysical analysis(9), the molecular basis of autoregulation remains unclear, although a putative Ca2+-binding EF-hand motif(11,12) and a nearby consensus calmodulin-binding isoleucine-glutamine ('IQ') motif(13,14) in the carboxy terminus of the alpha(1C) channel subunit have been implicated(12,14-16). Here we show that calmodulin is a critical Ca2+ sensor for both inactivation and facilitation, and that the nature of the modulatory effect depends on residues within the IQ motif important for calmodulin binding. Replacement of the native isoleucine by alanine removed Ca2+-dependent inactivation and unmasked a strong facilitation; conversion of the same residue to glutamate eliminated both forms of autoregulation. These results indicate that the same calmodulin molecule may act as a Ca2+ sensor for both positive and negative modulation.
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页码:159 / 162
页数:4
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