State-Dependent Inhibition of Inactivation-Deficient CaV1.2 and CaV2.3 Channels By Mibefradil

@article{Bernatchez2001StateDependentIO,
  title={State-Dependent Inhibition of Inactivation-Deficient CaV1.2 and CaV2.3 Channels By Mibefradil},
  author={G{\'e}rald Bernatchez and Rémy Sauvé and Lucie Parent},
  journal={The Journal of Membrane Biology},
  year={2001},
  volume={184},
  pages={143-159}
}
Abstract. The structural determinants of mibefradil inhibition were analyzed using wild-type and inactivation-modified CaV1.2 (α1C) and CaV2.3 (α1E) channels. Mibefradil inhibition of peak Ba2+ currents was dose- and voltage-dependent. An increase of holding potentials from −80 to −100 mV significantly shifted dose-response curves toward higher mibefradil concentrations, namely from a concentration of 108 ± 21 μm (n= 7) to 288 ± 17 μm (n= 3) for inhibition of half of the Cav1.2 currents (IC50… Expand
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References

SHOWING 1-10 OF 69 REFERENCES
Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels.
TLDR
A series of mutations at position R378 suggest that positively charged residues could promote voltage-dependent inactivation, which could play a significant role in the inactivation of Ca(V)1.2 and CaV2.3 channels. Expand
Mechanism of voltage‐ and use‐dependent block of class A Ca2+ channels by mibefradil
TLDR
Voltage‐dependent slow recovery from open state‐dependent block provides a molecular basis for understanding the cardiovascular profile of mibefradil such as selectivity for vasculature and relative lack of negative inotropic effects. Expand
State- and isoform-dependent interaction of isradipine with the α1C L-type calcium channel
TLDR
The results suggest that the higher DHP selectivity of the α1Cb versus theα1Ca channel is caused by the structural difference in the binding site and not by different transitions between resting, open and inactivated states. Expand
Potent inhibition of a recombinant low voltage-activated Ca(2+) channel by SB-209712.
TLDR
SB-209712 (1,6,bis¿1-[4-(3-phenylpropyl)piperidinyl]¿hexane), a compound originally developed as a high voltage-activated Ca(2+) channel blocker, proved to be a more potent T-type channel antagonist, exhibiting an IC(50) in the region of 500 nM. Expand
Regulation of the calcium channel α1G subunit by divalent cations and organic blockers
Abstract The pharmacological properties of the expressed murine T-type α1G channel were characterized using the whole cell patch clamp configuration. Ba2+ or Ca2+ were used as charge carriers. BothExpand
Effect of mibefradil on voltage-dependent gating and kinetics of T-type Ca(2+) channels in cortisol-secreting cells.
TLDR
The enhanced potency of mibefradil with sustained or repetitive depolarizations, its shifting of the steady-state inactivation curve, and its slowing of recovery all indicate that this drug preferentially interacts with Ca(2+) channels in the open or inactivated state. Expand
Pharmacological properties of Cav3.2, a low voltage-activated Ca2+ channel cloned from human heart
TLDR
The many similarities between the two channels support the contention that Cav3.2 encodes cardiac T-type Ca2+ channels, which was suggested to be the case in guinea pig atrial myocytes. Expand
Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels
TLDR
It is concluded that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil. Expand
Mutations in the EF-hand motif impair the inactivation of barium currents of the cardiac alpha1C channel.
TLDR
The results showed that E1537 mutations impaired voltage-dependent inactivation and suggest that the proximal part of the C-terminus may play a role in voltage- dependent inactivation in L-type alpha1C channels. Expand
Fast Inactivation of Voltage-dependent Calcium Channels
TLDR
Overall, the data are consistent with a mechanism in which inactivation of voltage-dependent calcium channels may occur via docking of the I-II linker region to a site comprising, at least in part, the domain II and III S6 segments. Expand
...
1
2
3
4
5
...