Single-Channel Pharmacology of Mibefradil in Human Native T-Type and Recombinant Ca<sub>v</sub>3.2 Calcium Channels

Michels, Guido; Matthes, Jan; Handrock, Renate; Kuchinke, Ute; Groner, Ferdi; Cribbs, Leanne L.; Pereverzev, Alexey; Schneider, Toni; Perez‐Reyes, Edward; Herzig, Stefan

doi:10.1124/mol.61.3.682

Cited by 31 publications

(30 citation statements)

References 33 publications

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“…In single-channel recordings, mibefradil inhibited the T-type Ca 2+ channel in the openchannel state (36). Contrary to this report, the inhibition was enhanced by a holding potential at which the T-type Ca 2+ channel is inactivated, suggesting that mibefradil has a higher affinity for inactivated states in the whole cell configuration (37).…”

Section: +contrasting

confidence: 54%

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

et al. 2012

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Abstract. We examined the effects of mibefradil, a T-type Ca 2+ channel inhibitor, on voltagedependent K + (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch clamp technique. Mibefradil reduced the Kv current amplitude in a dose-dependent manner, with an apparent K d value of 1.08 μM. Kv current inhibition by mibefradil was highly voltagedependent over the full activation voltage range (−30 to +10 mV). The decay rate of Kv channel inactivation was accelerated by mibefradil without altering the kinetics of current activation. The rate constants of association and dissociation were 2.23 ± 0.07 μM , respectively. Mibefradil had no significant effect on the steady-state activation or inactivation curves. In the presence of mibefradil, the recovery time constant from inactivation was decreased, and the application of train pulses (1 or 2 Hz) increased mibefradil-induced Kv channel inhibition, suggesting that the inhibitory effects of mibefradil were use-dependent. The inhibitory effect of mibefradil on Kv channels was unaffected by extracellular Ca 2+ -free conditions. Moreover, the absence of ATP inside the pipette did not alter the blocking effect of mibefradil. Therefore, we suggest that mibefradil directly inhibited the Kv current, independently of Ca 2+ channel inhibition.

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Section: +contrasting

confidence: 54%

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

et al. 2012

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“…2,12-15 However, we do not consider these and our results contradictory because the difference in inhibition may be due, at least partly, to different experimental conditions, given that for other channels and compounds, a lower sensitivity in cell-attached versus whole-cell configuration also has been reported. 33,34 Moreover, activation of both mCa1 and mCa2 by spermine further supports their Ca 2ϩ channel identity of the MCU and non-MCU type. 26 Although mitochondrial dysfunction in disease and aging has been related mainly to direct alterations of the respiratory chain or ⌬⌿, 35,36 here we demonstrate reduced function of mitochondrial Ca 2ϩ -channels and thus of an indirect modulator of energy and reactive oxygen species production in a disease known to be associated with profound changes in intracellular Ca 2ϩ homeostasis and metabolism.…”

Section: Discussionmentioning

confidence: 86%

Regulation of the Human Cardiac Mitochondrial Ca ²⁺ Uptake by 2 Different Voltage-Gated Ca ²⁺ Channels

et al. 2009

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Background— Impairment of intracellular Ca 2+ homeostasis and mitochondrial function has been implicated in the development of cardiomyopathy. Mitochondrial Ca 2+ uptake is thought to be mediated by the Ca 2+ uniporter (MCU) and a thus far speculative non-MCU pathway. However, the identity and properties of these pathways are a matter of intense debate, and possible functional alterations in diseased states have remained elusive. Methods and Results— By patch clamping the inner membrane of mitochondria from nonfailing and failing human hearts, we have identified 2 previously unknown Ca 2+ -selective channels, referred to as mCa1 and mCa2. Both channels are voltage dependent but differ significantly in gating parameters. Compared with mCa2 channels, mCa1 channels exhibit a higher single-channel amplitude, shorter openings, a lower open probability, and 3 to 5 subconductance states. Similar to the MCU, mCa1 is inhibited by 200 nmol/L ruthenium 360, whereas mCa2 is insensitive to 200 nmol/L ruthenium 360 and reduced only by very high concentrations (10 μmol/L). Both mitochondrial Ca 2+ channels are unaffected by blockers of other possibly Ca 2+ -conducting mitochondrial pores but were activated by spermine (1 mmol/L). Notably, activity of mCa1 and mCa2 channels is decreased in failing compared with nonfailing heart conditions, making them less effective for Ca 2+ uptake and likely Ca 2+ -induced metabolism. Conclusions— Thus, we conclude that the human mitochondrial Ca 2+ uptake is mediated by these 2 distinct Ca 2+ channels, which are functionally impaired in heart failure. Current properties reveal that the mCa1 channel underlies the human MCU and that the mCa2 channel is responsible for the ruthenium red–insensitive/low-sensitivity non-MCU–type mitochondrial Ca 2+ uptake.

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“…Mibefradil block of both HVA and LVA channels is state dependent (41,278). Single-channel measurements indicate the presence of open channel block, and in addition, a longer lasting block that results in a reduction in active sweeps (280). Whole cell measurements indicate that inhibition is enhanced by holding the membrane at potentials where T-type channels inactivate, suggesting the drug has higher affinity for inactivated states.…”

Section: A Antihypertensivesmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Single-Channel Pharmacology of Mibefradil in Human Native T-Type and Recombinant Ca_v3.2 Calcium Channels

Cited by 31 publications

References 33 publications

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Regulation of the Human Cardiac Mitochondrial Ca ²⁺ Uptake by 2 Different Voltage-Gated Ca ²⁺ Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Single-Channel Pharmacology of Mibefradil in Human Native T-Type and Recombinant Cav3.2 Calcium Channels

Cited by 31 publications

References 33 publications

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Regulation of the Human Cardiac Mitochondrial Ca 2+ Uptake by 2 Different Voltage-Gated Ca 2+ Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Resources

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Single-Channel Pharmacology of Mibefradil in Human Native T-Type and Recombinant Ca_v3.2 Calcium Channels

Regulation of the Human Cardiac Mitochondrial Ca ²⁺ Uptake by 2 Different Voltage-Gated Ca ²⁺ Channels