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Papers In Press, published online ahead of print September 12, 2005
Department of Pharmacology and Toxicology, University of Vienna, Wien A-1090
Corresponding Author: steffen.hering{at}univie.ac.at
The mechanism of channel opening for voltage-gated calcium channels is poorly understood. The importance of a conserved isoleucine residue in the pore-lining segment IIS6 has recently been highlighted by functional analyses of a mutation (I745T) in the CaV1.4 channel causing severe visual impairment (1). In the present study we analysed the influence of amino acids in segment IIS6 on gating of the Cav1.2 channel. Substitution of I781, the Cav1.2 residue corresponding to I745 in Cav1.4, by residues of different hydrophobicity, size and polarity shifted channel activation in the hyperpolarising direction (I781P>I781T> I781N>I781A>I781L). As I781P caused the most dramatic shift (-37 mV), substitution with this amino acid was used to probe the role of other residues in IIS6 in the process of channel activation. Mutations revealed a high correlation between the midpoint voltages of activation and inactivation. A unique kinetic phenotype was observed for residues 779-782 (LAIA) located in the lower third of segment IIS6: a shift in the voltage-dependence of activation was accompanied by a deceleration of activation at hyperpolarised potentials, a deceleration of deactivation at all potentials (I781P and I781T), and decreased inactivation. These findings indicate that I781 substitutions both destabilise the closed conformation and stabilise the open conformation of CaV1.2. Moreover there may be a flexible centre of helix bending at positions 779-782 of CaV1.2. These four residues are completely conserved in high-voltage-activated calcium channels suggesting that these channels may share a common mechanism of gating.
J. Biol. Chem, 10.1074/jbc.M507013200
Submitted on June 28, 2005
Revised on September 9, 2005
Accepted on September 12, 2005
Structural determinants of L-type channel activation in segment IIS6 revealed by a retinal disorder
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