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Cardiovascular Research Institute, Department of Biochemistry and Biophysics, and Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158

Correspondence to Daniel L. Minor Jr.: daniel.minor{at}ucsf.edu

Two processes dominate voltage-gated calcium channel (Ca_V) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The Ca_Vβ/Ca_V1-I-II loop and Ca²⁺/calmodulin (CaM)/Ca_V1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–-interaction domain (AID) linker provides a rigid connection between the pore and Ca_Vβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate Ca_V1.2 (L-type) and Ca_V2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt Ca_Vβ/I-II association sharply decelerate CDI and reduce a second Ca²⁺/CaM/Ca_V1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, Ca_Vβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both Ca_Vβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring Ca_Vβ and an intact IS6-AID linker.

Abbreviations used in this paper: AID, -interaction domain; CaM, calmodulin; Ca_V, voltage-gated calcium channel; CD, circular dichroism; CDF, calcium-dependent facilitation; CDI, calcium-dependent inactivation; TEV, tobacco etch mosaic virus; TFE, trifluoroethanol; VDI, voltage-dependent inactivation.

© 2009 Findeisen and Minor
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