Key result
The α1C I-II loop strongly increases channel surface density via an acidic-residue ER export motif, while β-dependent current increase requires four α1C intracellular domains including the C-terminus.
The study reveals that β-subunit binding to the α1C I-II loop causes a C-terminus-dependent rearrangement that shifts the balance between export and retention signals, facilitating CaV1.2 channel membrane trafficking.
No immediate clinical implications; leaves open whether targeting α1C domains can therapeutically modulate CaV1.2 trafficking.
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.
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Fang et al. (2011) studied this question. Chimeras featuring substitutions of intracellular loops/termini of α1C into CaV3.1-α1G channel was evaluated on Channel surface density and β-dependent increase in current. The α1C I-II loop strongly increases channel surface density via an acidic-residue ER export motif, while β-dependent current increase requires four α1C intracellular domains including the C-terminus.
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