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

  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},
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
Modulation and Pharmacology of Low Voltage-Activated (“T-Type”) Calcium Channels
  • A. Yunker
  • Biology, Medicine
  • Journal of bioenergetics and biomembranes
  • 2003
Comparison of the responses of recombinant and native LVAs to pharmacological agents and endogenous modulatory molecules will lead to a better understanding of LVAs in normal and diseased cells. Expand
The CaV3.1 T-type Ca2+channel contributes to voltage-dependent calcium currents in rat outer hair cells
Calcium currents through voltage-dependent Ca2+channels (VDCCs) in mammalian outer hair cells (OHCs) are generally considered to possess the pharmacological properties of L-typeExpand
The Role of the GX9GX3G Motif in the Gating of High Voltage-activated Ca2+ Channels*
The mutational analysis highlights the role of the GX3G motif in the voltage-dependent activation and inactivation gating of HVA CaV channels with the distal glycine residue being mostly involved in the in activation gating. Expand
Negatively charged residues in the N-terminal of the AID helix confer slow voltage dependent inactivation gating to CaV1.2.
The unique role of E461, E462, and D463 in the I-II linker in the VDI gating of high-voltage activated CaV1.2 channels is highlighted, confirming that CaVbeta2a and E462R modulate VDI through a common pathway, albeit in opposite directions. Expand
A specific tryptophan in the I-II linker is a key determinant of beta-subunit binding and modulation in Ca(V)2.3 calcium channels.
Results suggest that W386 is critical for beta-subunit binding and modulation of HVA Ca(2+) channels. Expand
The C-terminal Residues in the Alpha-interacting Domain (AID) Helix Anchor CaVβ Subunit Interaction and Modulation of CaV2.3 Channels*
Molecular replacement analyses carried out using a three-dimensional homology model of the AID helix from CaV2.3 suggests that a high degree of hydrophobicity and a restrained binding pocket could account for the strict structural specificity of the interaction site found at position Ile14. Expand
Voltage-gated Ca2+ currents are necessary for slow-wave propagation in the canine gastric antrum.
These experiments show that voltage-dependent Ca(2+) entry is obligatory for the upstroke phase of slow waves and active propagation in canine gastric antral muscles. Expand
Étude moléculaire du syndrome du long QT8: rôle des résidus glycine dans la fonction du canal Ca1̌.2
The L-type Ca2 channel plays a key raie in excitation-contraction coupling of ventricular cardiac myocytes. It has been recently shown that mutations in two conserved glycine residues (G402S & G406R)Expand
Calcium channel blockers and calcium channels
In 1883, Ringer showed that to get isolated hearts to contract, it was necessary to have Ca2+ ions in the perfusion medium [421]. This was the first demonstration of the critical role of calcium inExpand
Drug targets in the voltage-gated calcium channel family: why some are and some are not.
  • D. Triggle
  • Medicine, Computer Science
  • Assay and drug development technologies
  • 2003
The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension, but small molecule equivalents of the L- type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. Expand


Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels.
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
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
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.
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.
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
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Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels
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.
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
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