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Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists
Abstract:
Cardiac calcium channel activity is markedly increased by beta-adrenergic agents or calcium agonists such as Bay K 8644. The molecular mechanisms underlying these important modulatory effects have been studied with patch clamp techniques by several groups. This paper presents new experiments and reviews published evidence from fluctuation analysis of whole cell calcium current and unitary recordings of single calcium channel activity. Two different factors underlie the enhancement of calcium channel activity seen with beta-stimulation or cyclic AMP: (1) increased availability of calcium channels, expressed in whole cell recordings as an increase in the number of functional channels and in single channel recordings as an increase in the proportion of non-blank sweeps. (2) changes in opening probability, due to alteration of the fast kinetics of channel opening and closing. Both factors contribute to the beta-adrenergic enhancement in frog, rat, and guinea-pig ventricular cells although their quantitative importance is somewhat variable. Unlike beta-adrenergic agents, calcium agonists such as Bay K 8644 promote a mode of channel gating that is characterized by long openings and short closings, seen only rarely in control or with beta-stimulation.
Insights
Beta-adrenergic stimulation and calcium agonists like Bay K 8644 increase cardiac calcium channel activity. This occurs through more available channels and altered opening probabilities, with distinct gating modes for each agent.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
- Ion Channel Biophysics
Background:
- Beta-adrenergic agents and calcium agonists modulate cardiac calcium channel activity.
- Understanding these modulatory mechanisms is crucial for cardiovascular research.
Purpose of the Study:
- To elucidate the molecular mechanisms behind beta-adrenergic and calcium agonist effects on cardiac calcium channels.
- To differentiate the contributions of channel availability and gating kinetics to enhanced calcium currents.
Main Methods:
- Patch clamp techniques, including whole-cell calcium current fluctuation analysis.
- Unitary recordings of single calcium channel activity.
- Comparative analysis of beta-adrenergic agents and the calcium agonist Bay K 8644.
Main Results:
- Beta-adrenergic stimulation increases cardiac calcium channel activity by enhancing channel availability and altering opening probability.
- Calcium agonists like Bay K 8644 induce a distinct gating mode characterized by prolonged openings.
- Both mechanisms contribute to beta-adrenergic enhancement across species (frog, rat, guinea-pig), with variable quantitative importance.
Conclusions:
- Cardiac calcium channel activity is regulated by distinct mechanisms under beta-adrenergic stimulation versus calcium agonism.
- Increased channel availability and altered gating kinetics are key factors in beta-adrenergic modulation.
- Bay K 8644 exhibits unique gating properties distinct from beta-adrenergic effects.