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Involvement of Protein Kinase C in the Coupling between the V₁ Vasopressin Receptor and Phospholipase C in Rat Glomerulosa Cells: Effects on Aldosterone Secretion

Faculte de Médecine, Service d'Endocrinologie, Département de Médecine, Université de Sherbrooke, Centre Hospitalier Universitaire Sherbrooke, Québec J1H 5N4, Canada
Centre CNRS-INSERM de Pharmacologie-Endocrinologie 34094 Montpellier Cedex 2, France

Address all correspondence and requests for reprints to: Dr. Nicole Gallo-Payet, Department of Medicine and Endocrinology, University of Sherbrooke Faculty of Medicine, 3001 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4.

Abstract

We have previously shown that arginine vasopressin (AVP) possesses specific binding sites on rat adrenal glomerulosa cells and stimulates phosphoinositide breakdown and accumulation of inositol phosphates (IP) and diacylglycerol. Kinetic experiments also revealed that the production of IP declines rapidly under hormonal stimulation, even in the presence of Ca²⁺ in the external medium. In the present investigation, we studied the effects of a protein kinase C (PKC) activator phorbol ester (PDBu) on AVP-sensitive accumulation of IP. Experiments were conducted on glomerulosa cells cultured for 3 days. Results show that short term preincubation (5–10 min) with PDBu inhibits AVP-stimulated IP accumulation by 50% (ED₅₀) = 2.6 ± 0.9 nM). PKC most likely acts on the coupling between AVP receptor and the G-protein since PDBu reduces AVP-sensitive phospholipase C but does not alter either NaF-sensitive phospholipase C, AVP binding, or inositol lipid pools. However, after a 1- or 2-h preincubation with AVP or PDBu, a decrease in both IP accumulation and AVP binding capacity is observed. With regard to aldosterone secretion, PDBu alone stimulates hormone output, but when added simultaneously with AVP, it inhibits AVP-stimulated aldosterone secretion by 70%. If cells are allowed a resting period of 14 h after AVP or PDBu treatment, the AVP response (IP accumulation, AVP binding, and aldosterone output) is recovered and even enhanced. All these effects are specific since the inactive phorbol ester 4PDD is inactive, and staurosporine (a PKC inhibitor) reverses the PDBu effect. AVP stimulates transiently the translocation of PKC from the cytosol to the membrane, suggesting that the effect observed with PDBu reflects the effect of endogenous PKC stimulated by AVP. These results outline the complexities involved during hormonal stimulation and, at the same time, homologous desensitization phenomena. On one hand, acute treatment with PDBu—which induces PKC activation—is able to stimulate aldosterone secretion but at the same time initiate desensitization, since phorbol ester uncouples the AVP receptor from the coupling G protein. This suggests that PKC may participate in the first step of homologous desensitization. On the other hand, a 2-h incubation with PDBu induces a loss of AVP binding sites. This may represent the second step of homologous desensitization. Finally, a long term treatment with PDBu completely inactivates PKC, hence enabling AVP to further stimulate aldosterone secretion.

Received January 28, 1991.

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