Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 33, Pages 30794-30802Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M104959200
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Funding
- NHLBI NIH HHS [K08 HL03743, K08 HL003743-04, K08 HL003743-06, K08 HL003743-03, K08 HL003743-05] Funding Source: Medline
- NIGMS NIH HHS [GM58234] Funding Source: Medline
- NINDS NIH HHS [NS24067] Funding Source: Medline
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Ca2+-dependent inactivation (CDI) of L-type Ca2+ channels plays a critical role in controlling Ca2+ entry and downstream signal transduction in excitable cells. Ca2+-insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, suggesting that CaM acts as a resident Ca2+ sensor. However, it is not known how the Ca2+ sensor is constitutively tethered. We have found that the tethering of Ca2+-insensitive CaM was localized to the C-terminal tail of arc, close to the CDI effector motif, and that it depended on nanomolar Ca2+ 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 Ca2+-independent inactivation. Synthetic peptides containing these sequences displayed differences in CaM-binding properties, both in affinity and Ca2+ 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.
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