Abstract
When the dose-response curve of adrenocorticotropin (ACTH)-induced aldosterone secretion is compared to that of ACTH-induced intracellular cAMP, the ED50 for intracellular cAMP is more than 10 times as high as that for aldosterone production. In contrast, the dose-response curve of forskolin-induced aldosterone secretion correlates well with that for forskolin-induced intracellular cAMP. ACTH, but not forskolin, increases calcium influx into glomerulosa cells without inducing the mobilization of calcium from an intracellular pool. The effect of ACTH on calcium influx is dose-dependent and ED50 is 3.5 X 10(-11) M. In a perifusion system, the effect of 1 nM ACTH on aldosterone secretion is much greater than that of 1 microM forskolin, even though these two stimulators induce identical increases in the intracellular cAMP. Perifusion with combined A23187 (50 nM) and forskolin (1 microM) stimulates aldosterone secretion to a value comparable to that induced by 1 nM ACTH. Likewise, BAY K 8644 (1 nM), which induces a comparable increase in calcium influx, potentiates the effect of 1 microM forskolin. When the intracellular [Ca2+] is fixed at either 100 or 300 nM, forskolin-stimulated intracellular cAMP content is identical, but ACTH-stimulated intracellular cAMP content at 100 nM [Ca2+]i is 60% of that at 300 nM [Ca2+]i. Both the ACTH- and forskolin-induced aldosterone secretion rate is higher at 300 nM than at 100 nM [Ca2+]i. These results indicate that ACTH stimulates calcium influx, that calcium potentiates ACTH-induced but not forskolin-induced cAMP generation, and that Ca2+ and cAMP act as synarchic messengers in ACTH-mediated aldosterone secretion.
Highlights
When the extracellular concentration of calcium is reduced, the aldosterone secretory response to ACTH is impaired and is completelyabolished in the absence of extracellular calcium [7].The role of calcium entry in the action of ACTH has been combined A23187 (50 nM) and forskolin (1 PM) stimu- indirectly demonstrated in studies using calcium channel lates aldosterone secretion to a value comparable to blockers [6, 8,9,10]
[Ca2+Ii.These results indicate that ACTH stimulates dibutyryl CAMP-induced aldosterone production is reduced calcium influx, that calcium potentiates ACTH-in- by removal of extracellular calcium [7] or by the addition of duced but not forskolin-induced cAMP generation, and a calmodulin inhibitor [11, 12]
Our results indicate that ACTH increases calcium influx into glomerulosa cells, that this calcium influx is coupled to the activation of adenylate cyclase by ACTH, and that theintracellular messengers, cAMP and dependent manner,and at highdoses, forskolin is a more potentstimulator of aldosterone production than ACTH
Summary
The present results confirm and extend the evidence in support of dual messenger function in ACTH action on adrenal cortical steroidogenesis in either fasciculata or glomerulosa cells. The results are against this conclusion because when forskolin, a direct activator of the cyclase, is employedas agonist there is a very close correlation between intracellular cAMP contentand rate of steroid hormone production whereas with ACTH as agonist, there is a dissociation between the two. The concentrations of ACTH required to induce this change in calcium influx are an order of magnitude lower than those necessary to induce an activation of adenylate cyclase These data are consistent with the proposals of Yanagibashi [17] and others [13,14,15] that there are two distinct classes of ACTH receptors on fasciculata cells, one a high affinity low capacity class linked to thecalcium messengersystem and theother alower affinity higher capacity class linked to thecAMP messenger system
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