A novel molecular inactivation determinant of voltage-gated CaV1.2 L-type Ca2+ channel

Neuroscience
A LivnehD Atlas

Abstract

The inactivation of voltage-gated L-type Ca(2+) channels (Ca(V)1) regulates Ca(2+) entry and controls intracellular Ca(2+) levels that are essential for cellular activity. The molecular entities implicated in L-channel (Ca(V)1.2) inactivation are not fully identified. Here we show for the first time the functional impact of one of the two highly conserved clusters of six negatively charged glutamates and aspartate (802-807; poly ED motif) at the II-III loop of the alpha 1 subunits of rabbit of Ca(v)1.2, alpha(1)1.2 and alpha(1)1.2 DeltaN60-Delta1733) on voltage-dependent inactivation. Mutation of the poly ED motif to alanine or glutamine/asparagine greatly enhanced voltage-dependent inactivation, shifting the voltage dependence to negative potentials by >50 mV and conferring a neuronal like inactivation kinetics onto Ca(V)1.2. The large shift in the midpoint of inactivation of the steady-state inactivation kinetics was observed also in Ca(2+) or Ba(2+) and was not altered by the beta2A subunit. Missing from the fast inactivating neuronal P/Q (Ca(V)2.1)-, N (Ca(V)2.2)- or R (Ca(V)2.3)-type channels and modulating Ca(V)1.2 inactivation kinetics, the poly ED motif is likely to be a specific L-type Ca(2+) channels inactivating doma...Continue Reading

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Citations

Feb 6, 2008·Proceedings of the National Academy of Sciences of the United States of America·Curtis F Barrett, Richard W Tsien
Apr 1, 2011·Trends in Pharmacological Sciences·Annalisa ZuccottiAntonella Pirone
Jun 9, 2016·Journal of Cellular and Molecular Medicine·Ben AvinerYoram Grossman
Mar 9, 2007·Journal of Neurophysiology·Jethro JonesKevin J Staley

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