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Novel mechanism of voltage-dependent gating in L-type calcium channels
1Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, Massachusetts 02115.
Abstract:
Activation of voltage-dependent calcium channels by membrane depolarization triggers a variety of key cellular responses, such as contraction in heart and smooth muscle and exocytotic secretion in endocrine and nerve cells. Modulation of calcium channel gating is believed to be the mechanism by which several neurotransmitters, hormones and therapeutic agents mediate their effects on cell function. Here we describe a novel type of voltage-dependent equilibrium between different gating patterns of dihydropyridine-sensitive (L-type) cardiac Ca2+ channels. Strong depolarizations drive the channel from its normal gating pattern into a mode of gating characterized by long openings and high open probability. The rate constants for conversions between gating modes, estimated from single channel recordings, are much slower than normal channel opening and closing rates, but the equilibrium between modes is almost as steeply voltage-dependent as channel activation and deactivation at more negative potentials. This new mechanism of voltage-dependent gating can explain previous reports of activity-dependent Ca2+ channel potentiation in cardiac and other cells and forms a potent mechanism by which Ca2+ uptake into cells could be regulated.
Insights
Voltage-dependent calcium channels exhibit a novel gating equilibrium. Strong depolarizations shift these channels to a mode with prolonged openings, regulating cellular calcium uptake.
Area of Science:
- Cardiology
- Neuroscience
- Cellular Physiology
Background:
- Voltage-dependent calcium channels mediate crucial cellular functions like muscle contraction and neurotransmitter release.
- Modulation of calcium channel gating is a key mechanism for various signaling molecules and drugs.
Purpose of the Study:
- To identify and characterize a novel voltage-dependent gating mechanism in dihydropyridine-sensitive (L-type) cardiac calcium channels.
- To elucidate how strong depolarizations alter calcium channel gating patterns and influence cellular responses.
Main Methods:
- Analysis of single channel recordings from cardiac L-type calcium channels.
- Estimation of rate constants for transitions between different gating modes.
- Assessment of the voltage-dependence of the equilibrium between gating modes.
Main Results:
- A novel voltage-dependent equilibrium between distinct gating modes of L-type cardiac Ca2+ channels was identified.
- Strong membrane depolarizations induce a shift to a gating mode with significantly longer openings and higher open probability.
- The inter-modal conversion rates are slower than typical gating kinetics, yet the equilibrium is highly voltage-dependent.
Conclusions:
- This newly described gating mechanism provides an explanation for activity-dependent potentiation of calcium channels observed in cardiac and other cell types.
- This voltage-dependent gating equilibrium represents a significant regulatory mechanism for cellular calcium influx.