PubMed 21746784

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Cav3.1

Title: Mechanism of auxiliary β-subunit-mediated membrane targeting of L-type (Ca(V)1.2) channels.

Authors: Kun Fang, Henry M Colecraft

Journal, date & volume: J. Physiol. (Lond.), 2011 Sep 15 , 589, 4437-55

PubMed link:

Ca(2+) influx via Ca(V)1/Ca(V)2 channels drives processes ranging from neurotransmission to muscle contraction. Association of a pore-forming α(1) and cytosolic β is necessary for trafficking Ca(V)1/Ca(V)2 channels to the cell surface through poorly understood mechanisms. A prevalent idea suggests β binds the α(1) intracellular I-II loop, masking an endoplasmic reticulum (ER) retention signal as the dominant mechanism for Ca(V)1/Ca(V)2 channel membrane trafficking. There are hints that other α(1) subunit cytoplasmic domains may play a significant role, but the nature of their potential contribution is unclear. We assessed the roles of all intracellular domains of Ca(V)1.2-α(1C) by generating chimeras featuring substitutions of all possible permutations of intracellular loops/termini of α(1C) into the β-independent Ca(V)3.1-α(1G) channel. Surprisingly, functional analyses demonstrated α(1C) I-II loop strongly increases channel surface density while other cytoplasmic domains had a competing opposing effect. Alanine-scanning mutagenesis identified an acidic-residue putative ER export motif responsible for the I-II loop-mediated increase in channel surface density. β-dependent increase in current arose as an emergent property requiring four α(1C) intracellular domains, with the I-II loop and C-terminus being essential. The results suggest β binding to the α(1C) I-II loop causes a C-terminus-dependent rearrangement of intracellular domains, shifting a balance of power between export signals on the I-II loop and retention signals elsewhere.