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J Biol Chem. August 17, 2001; 276 (33): 30794-802.

Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of L-type Ca2+ channels.

Pitt GS , Z├╝hlke RD , Hudmon A , Schulman H , Reuter H , Tsien RW .

Ca(2+)-dependent inactivation (CDI) of L-type Ca(2+) channels plays a critical role in controlling Ca(2+) entry and downstream signal transduction in excitable cells. Ca(2+)-insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, suggesting that CaM acts as a resident Ca(2+) sensor. However, it is not known how the Ca(2+) sensor is constitutively tethered. We have found that the tethering of Ca(2+)-insensitive CaM was localized to the C-terminal tail of alpha(1C), close to the CDI effector motif, and that it depended on nanomolar Ca(2+) concentrations, likely attained in quiescent cells. Two stretches of amino acids were found to support the tethering and to contain putative CaM-binding sequences close to or overlapping residues previously shown to affect CDI and Ca(2+)-independent inactivation. Synthetic peptides containing these sequences displayed differences in CaM-binding properties, both in affinity and Ca(2+) dependence, leading us to propose a novel mechanism for CDI. In contrast to a traditional disinhibitory scenario, we suggest that apoCaM is tethered at two sites and signals actively to slow inactivation. When the C-terminal lobe of CaM binds to the nearby CaM effector sequence (IQ motif), the braking effect is relieved, and CDI is accelerated.

PubMed ID: 11408490
Article link: J Biol Chem.
Grant support: GM58234 NIGMS NIH HHS , K08 HL003743-03 NHLBI NIH HHS , K08 HL003743-04 NHLBI NIH HHS , K08 HL003743-05 NHLBI NIH HHS , K08 HL003743-06 NHLBI NIH HHS , K08 HL03743 NHLBI NIH HHS , NS24067 NINDS NIH HHS , K08 HL003743 NHLBI NIH HHS

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