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Physiological and pharmacological correlates of calcium antagonist receptors
J A Wagner1, I J Reynolds, S H Snyder
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Abstract:
We studied voltage-sensitive and Na-dependent Ca2+ flux into synaptosomes as well as Na-dependent influx in cardiac sarcolemmal vesicles. Rapid, voltage-sensitive 45Ca2+ influx into synaptosomes is blocked by cadmium (IC50 1 microM) and the novel peptide toxin omega-conotoxin GVIA (30% of uptake blocked by 50 pM toxin), but not by dihydropyridine and phenylalkylamine calcium antagonists, even though [3H]dihydropyridines and [3H]phenylalkylamines bind to synaptosomes. The toxin also blocks voltage-sensitive neurotransmitter release from synaptosomes. Sodium-dependent Ca2+ flux into synaptosomes and cardiac sarcolemmal vesicles is inhibited by selected antihistamines, neuroleptics, and tricyclic antidepressants. We can elicit neurotransmitter release from synaptosomes by changing the Na gradient; this neurotransmitter release is absolutely Ca2+-dependent and blocked by Na+/Ca2+ exchange inhibitors, thereby suggesting that physiological neurotransmitter release may have a Na+/Ca2+ exchange component. More potent Na+/Ca2+ exchange inhibitors may have cardiovascular roles as inotropic agents or antagonists of calcium-related injury to cardiomyocytes during reperfusion or other disease states.
Insights
This study reveals that calcium (Ca2+) influx into nerve terminals and cardiac cells is modulated by sodium (Na+) gradients and specific toxins. These findings suggest potential cardiovascular applications for Na+/Ca2+ exchange inhibitors.
Area of Science:
- Neuroscience
- Cardiovascular Physiology
- Biochemistry
Background:
- Calcium (Ca2+) influx is critical for neurotransmitter release and cardiac function.
- Voltage-sensitive and sodium-dependent Ca2+ transport mechanisms are key regulators of cellular excitability.
- Understanding these pathways is crucial for developing targeted therapeutics.
Purpose of the Study:
- To investigate the mechanisms of voltage-sensitive and Na+-dependent Ca2+ influx in synaptosomes and cardiac sarcolemmal vesicles.
- To identify potential modulators of Ca2+ flux, including peptide toxins and common pharmaceuticals.
- To explore the role of Na+/Ca2+ exchange in neurotransmitter release and its potential cardiovascular implications.
Main Methods:
- Utilized radiolabeled Ca2+ (45Ca2+) and neurotransmitter release assays in isolated synaptosomes.
- Employed cardiac sarcolemmal vesicles to study Na+-dependent Ca2+ influx.
- Investigated the effects of cadmium, omega-conotoxin GVIA, dihydropyridines, phenylalkylamines, antihistamines, neuroleptics, and tricyclic antidepressants on Ca2+ flux.
Main Results:
- Voltage-sensitive Ca2+ influx into synaptosomes was inhibited by cadmium and omega-conotoxin GVIA, but not by dihydropyridines or phenylalkylamines.
- Omega-conotoxin GVIA also blocked voltage-sensitive neurotransmitter release.
- Na+-dependent Ca2+ flux in both synaptosomes and cardiac vesicles was inhibited by antihistamines, neuroleptics, and tricyclic antidepressants.
- Neurotransmitter release was induced by altering the Na+ gradient and was Ca2+-dependent, suggesting a role for Na+/Ca2+ exchange.
Conclusions:
- Specific toxins like omega-conotoxin GVIA effectively block voltage-sensitive Ca2+ influx and neurotransmitter release.
- Certain pharmaceutical classes, including antihistamines and antidepressants, can modulate Na+-dependent Ca2+ flux.
- Na+/Ca2+ exchange may play a significant role in physiological neurotransmitter release.
- Development of potent Na+/Ca2+ exchange inhibitors could offer therapeutic benefits in cardiovascular conditions, such as heart failure or ischemia-reperfusion injury.