Calcium channel β-subunit binds to a conserved motif in the I–II cytoplasmic linker of the α1-subunit

Publisher Website
Google Scholar
Abstract
THE β-subunit is an integral component of purified voltage-sensitive Ca2+ channels1–3. Modulation of Ca2+ channel activity by the β-subunit, which includes significant increases in transmembrane current and/or changes in kinetics, is observed on coexpression of six α 1-subunit genes with four β-subunit genes in all α 1- β combinations tested4–12. Recent reports suggest that this regulation is not due to targeting of the α 1-subunit to the plasma membrane but is probably a result of a conformational change induced by the β-subunit11,13. Here we report that the β-subunit binds to the cytoplasmic linker between repeats I and II of the dihydropyridine-sensitive α 1-subunits from skeletal (α 1S) and cardiac muscles (α 1C-a), and also with the more distantly related neuronal α 1A and ω-conotoxin GVIA-sensitive aα 1B-subunits. Sequence analysis of the β-subunit binding site identifies a conserved motif (QQ-E--L-GY--WI---E) positioned 24 amino acids from the IS6 transmem-brane domain in each α 1-subunit. Mutations within this motif reduce the stimulation of peak currents by the β-subunit and alter inactivation kinetics and voltage-dependence of activation. Conser-vation of the β-subunit binding motif in these functionally distinct calcium channels suggests a critical role for the I-II cytoplasmic linker of the α 1-subunit in channel modulation by the β-subunit.