New determinant for the Ca-v beta(2) subunit modulation of the Ca(v)1.2 calcium channel

作者：Lao Qi Zong; Kobrinsky Evgeny; Harry Jo Beth; Ravindran Arippa; Soldatov Nikolai M^*

来源：Journal of Biological Chemistry, 2008, 283(23): 15577-15588.

DOI：10.1074/jbc.M802035200

Ca-v beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca-v beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca-v beta(2) subunit splice variants differentially modulate inactivation of Ca2+ currents (I-Ca). Previously we described beta(2 Delta g), a functionally active splice variant of human Ca-v beta(2) lacking MAGUK. By deletion analysis of beta(2 Delta g), we have now identified a 41-amino acid C-terminal essential determinant (beta 2CED) that stimulates ICa in the absence of Ca-v beta subunits and conveys a +20-mV shift in the peak of the I-Ca-voltage relationship. The beta 2CED is targeted by alpha(1C) to the plasma membrane, forms a complex with alpha(1C) but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the alpha(1C) subunit C terminus as a functionally relevant beta 2CED binding site. The beta 2CED interacts with LA/IQ in a Ca2+- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca-v beta(2)/alpha(1C) interactions is sufficient to support I-Ca. However, beta 2CED does not support Ca2+-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca2+-induced inactivation. The beta 2CED is conserved only in Ca-v beta(2) subunits. Thus, beta 2CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca-v beta(2)-subunit differential modulation of the Ca(v)1.2 calcium channel that in beta(2 Delta g) occurs without MAGUK.

• 出版日期2008-6-6