期刊
JOURNAL OF CELL BIOLOGY
卷 171, 期 3, 页码 537-547出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200505155
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- NHLBI NIH HHS [R01 HL071165] Funding Source: Medline
- NIGMS NIH HHS [R01 GM058234] Funding Source: Medline
- NINDS NIH HHS [R01 NS024067] Funding Source: Medline
Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for upregulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Ca(v)1.2) contributes to the positive force-frequency effect in the heart and is believed to involve the activation of Ca2+/calmodulin-dependent kinase II ( CaMKII). How CaMKII is activated and what its substrates are have not yet been determined. We show that the pore-forming subunit alpha(1C) ( Ca-v alpha 1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of alpha(1C) is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to alpha(1C), CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca2+/CaM dependent, explaining its ability to operate as a calcium spike frequency detector. These findings clarify the molecular basis of CDF and demonstrate a novel enzymatic mechanism by which ion channel gating can be modulated by activity.
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