Electrophysiology of Dihydropyridine Calcium Agonists

Bechem, Martin; Schramm, Matthias

doi:10.1007/978-3-642-73914-9_6

Cited by 4 publications

(1 citation statement)

References 12 publications

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“…The single channel measurements were all performed with Bay K 8644 present in the intracellular solution. This agonist increased the open lifetime of the L-type Ca channel (Hess et al, 1984), accompanied with significant changes in the voltage-dependent gating kinetics of the Ca channel in cardiac muscle (Bechem and Schramm, 1988). It is conceivable that part of the conditioning-induced fast gating of the Ca channel was due to the voltage-dependent binding of Bay K 8644 to the DHP receptor.…”

Section: Comparison With Measurements Of Lc~ In Skeletal Musclementioning

confidence: 96%

Fast activation of dihydropyridine-sensitive calcium channels of skeletal muscle. Multiple pathways of channel gating.

Gonzalez

Chen

1996

The Journal of General Physiology

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Dihydropyridine (DHP) receptors of the transverse tubule membrane play two roles in excitationcontraction coupling in skeletal muscle: (a) they function as the voltage sensor which undergoes fast transition to control release of calcium from sarcoplasmic reticulum, and (b)they provide the conducting unit of a slowly activating L-type calcium channel. To understand this dual function of the DHP receptor, we studied the effect of depolarizing conditioning pulse on the activation kinetics of the skeletal muscle DHP-sensitive calcium channels reconstituted into lipid bilayer membranes. Activation of the incorporated calcium channel was imposed by depolarizing test pulses from a holding potential of -80 mV. The gating kinetics of the channel was studied with ensemble averages of repeated episodes. Based on a first latency analysis, two distinct classes of channel openings occurred after depolarization: most had delayed latencies, distributed with a mode at 70 ms (slow gating); a small number of openings had short first latencies, <12 ms (fast gating). A depolarizing conditioning pulse to +20 mV placed 200 ms before the test pulse (-10 mV), led to a significant increase in the activation rate of the ensemble averaged-current; the time constant of activation went from "fin = 110 ms (reference) to T,,~ = 45 ms after conditioning. This enhanced activation by the conditioning pulse was due to the increase in frequency of fast open events, which was a steep function of the intermediate voltage and the interval between the conditioning pulse and the test pulse. Additional analysis demonstrated that fast gating is the property of the same individual channels that normally gate slowly and that the channels adopt this property after a sojourn in the open state. The rapid secondary activation seen after depolarizing prepulses is not compatible with a linear activation model for the calcium channel, but is highly consistent with a cyclical model. A six-state cyclical model is proposed for the DHP-sensitive Ca channel, which pictures the normal pathway of activation of the calcium channel as two voltagedependent steps in sequence, plus a voltage-independent step which is rate limiting. The model reproduced well the fast and slow gating modes of the calcium channel, and the effects of conditioning pulses. It is possible that the voltage-sensitive gating transitions of the DHP receptor, which occur early in the calcium channel activation sequence, could underlie the role of the voltage sensor and yield the rapid excitation-contraction coupling in skeletal muscle, through either electrostatic or allosteric linkage to the ryanodine receptors/calcium release channels.

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Section: Comparison With Measurements Of Lc~ In Skeletal Musclementioning

confidence: 96%

Fast activation of dihydropyridine-sensitive calcium channels of skeletal muscle. Multiple pathways of channel gating.

Gonzalez

Chen

1996

The Journal of General Physiology

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Dual action of prajmalium on the Ca currents in frog isolated cardiomyocytes

Álvarez

Vassort

1991

Journal of Molecular and Cellular Cardiology

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Antiarrhythmic drugs and cardiac ion channels: mechanisms of action

Carmeliet

Mubagwa

1998

Progress in Biophysics and Molecular Biology

106

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In this review a description and an analysis are given of the interaction of antiarrhythmic drugs with their molecular target, i.e. ion channels and receptors. Our approach is based on the concept of vulnerable parameter, i.e. the electrophysiological property which plays a crucial role in the genesis of arrhythmias. To prevent or stop the arrhythmia a drug should modify the vulnerable parameter by its action on channel or receptor targets. In the first part, general aspects of the interaction between drugs channel molecules are considered. Drug binding depends on the state of the channel: rested, activated pre-open, activated open, or inactivated state. The change in channel behaviour with state is presented in the framework of the modulated-receptor hypothesis. Not only inhibition but also stimulation can be the result of drug binding. In the second part a detailed and systematic description and an analysis are given of the interaction of drugs with specific channels (Na+, Ca2+, K+, "pacemaker") and non-channel receptors. Emphasis is given to the type of state-dependent block involved (rested, activated and inactivated state block) and the change in channel kinetics. These properties vary and determine the voltage- and frequency-dependence of the change in ionic current. Finally, the question is asked as to whether the available drugs by their action on channels and receptors modify the vulnerable parameter in the desired way to stop or prevent arrhythmias.

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Electrophysiology of Dihydropyridine Calcium Agonists

Cited by 4 publications

References 12 publications

Fast activation of dihydropyridine-sensitive calcium channels of skeletal muscle. Multiple pathways of channel gating.

Fast activation of dihydropyridine-sensitive calcium channels of skeletal muscle. Multiple pathways of channel gating.

Dual action of prajmalium on the Ca currents in frog isolated cardiomyocytes

Antiarrhythmic drugs and cardiac ion channels: mechanisms of action

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