A novel calmodulin site in the Cav1.2 N-terminus regulates calcium-dependent inactivation

作者：Simms Brett A; Souza Ivana Assis; Zamponi Gerald W^*

来源：Pflugers Archiv-European Journal of Physiology, 2014, 466(9): 1793-1803.

DOI：10.1007/s00424-013-1423-9

• Calcium channel
• Calmodulin
• CDI
• N-terminus
• NSCaTE
• Inactivation
• Cav1.2
• L-type
• IQ
• CaM

The L-type voltage-gated calcium channel Cav1.2 is important for excitation-contraction coupling in the heart, as well as CREB-mediated transcription in the brain. The ubiquitous calcium-binding protein calmodulin (CaM) is known to modulate calcium-dependent inactivation (CDI) of these channels, thus limiting the amount of calcium entering via Cav1.2 during prolonged or repetitive membrane depolarizations. The proximal N-terminus of Cav1.2 contains a CaM-binding site at residue W52 that is critical for a type of CDI that is mediated by the N-terminal lobe of CaM. Here, we identify a second CaM interaction site in the Cav1.2 N-terminus downstream of the W52 site that is formed by residue C106. We show by site-directed mutagenesis coupled with electrophysiological measurements that this region of the channel functionally partakes in N-lobe CDI, likely by acting as a gating transduction motif. Thus, our data indicate that calcium regulation of Cav1.2 channels is more complex than previously thought, and involves more than one region within the channel%26apos;s N-terminal domain.

• 出版日期2014-9