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Voltage-gated calcium currents have two opposing effects on the secretion of aldosterone
P Q Barrett1, E A Ertel, M M Smith
1Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
Abstract:
Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have investigated the roles of these two channel types in K(+)-induced aldosterone secretion. In whole cell voltage-clamp experiments, the spider toxin omega-agatoxin-IIIA (omega-Aga-IIIA) completely blocks L-type Ca2+ channels but has no effect on T-type Ca2+ channels. In contrast, Ni2+ and 1,4-dihydropyridines block both L- and T-type Ca2+ channels. Secretion induced by 7 mM extracellular K+ concentration ([K+]o) is unaffected by omega-Aga-IIIA but is strongly inhibited by Ni2+ or the 1,4-dihydropyridine, nitrendipine. This suggests that physiological increases in [K+]o stimulate aldosterone secretion primarily by enhancing Ca2+ entry through T-type Ca2+ channels. Surprisingly, secretion induced by 60 mM [K+]o is enhanced by omega-Aga-IIIA or Ni2+ and is inhibited by the L-type Ca2+ channel activator BAY K 8644. Nitrendipine (1 nM) also stimulates such secretion, although higher concentrations are inhibitory (concentration inhibiting 50% of maximal response approximately 30 nM). If extracellular Ca2+ concentration is reduced from 1.25 to 0.5 mM, secretion induced by 60 mM [K+]o is enhanced, and Ni2+ or low nitrendipine become inhibitory. Together, these results that L-type Ca2+ currents can reduce steroidogenesis and that the role of these currents was previously misconstrued because 1,4-dihydropyridines modify secretion by multiple mechanisms. Thus Ca2+ entry can function as a negative modulator of steroid secretion.
Insights
Potassium-induced aldosterone secretion is primarily mediated by T-type calcium channels at physiological levels. However, L-type calcium channels can inhibit steroidogenesis, with their role previously misunderstood due to drug interactions.
Area of Science:
- Endocrinology
- Molecular Physiology
- Ion Channel Biology
Background:
- Aldosterone secretion is regulated by extracellular potassium concentration ([K+]o).
- Calcium (Ca2+) influx through voltage-gated channels is crucial for this process.
- The specific roles of L-type and T-type Ca2+ channels in aldosterone secretion remain incompletely understood.
Purpose of the Study:
- To elucidate the distinct roles of L-type and T-type Ca2+ channels in potassium-stimulated aldosterone secretion.
- To investigate the mechanisms by which different Ca2+ channel subtypes modulate steroidogenesis.
Main Methods:
- Whole-cell voltage-clamp electrophysiology.
- Pharmacological manipulation using specific Ca2+ channel blockers (omega-agatoxin-IIIA, Ni2+, nitrendipine) and activators (BAY K 8644).
- Measurement of aldosterone secretion under varying extracellular K+ and Ca2+ concentrations.
Main Results:
- Physiological [K+]o-induced secretion is mediated by T-type Ca2+ channels, unaffected by L-type channel blockers.
- High [K+]o-induced secretion is paradoxically enhanced by L-type channel blockers and inhibited by L-type channel activators.
- Altered extracellular Ca2+ concentrations modulated the effects of channel blockers/activators, suggesting L-type Ca2+ currents negatively regulate steroidogenesis.
Conclusions:
- Aldosterone secretion is differentially regulated by T-type and L-type Ca2+ channels depending on extracellular K+ levels.
- L-type Ca2+ channel activity can act as a negative modulator of aldosterone synthesis and secretion.
- The complex effects of 1,4-dihydropyridines on secretion are due to multiple mechanisms, necessitating careful interpretation.