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Cholecystokinin (CCK) Stimulates Aldosterone Secretion from Human Adrenocortical Cells via CCK2 Receptors Coupled to the Adenylate Cyclase/Protein Kinase A Signaling Cascade

Department of Human Anatomy and Physiology, Section of Anatomy, University of Padua (G.M., R.S., G.G.N.), I-35121 Padua, Italy; Department of Histology and Embryology, School of Medicine (L.K.M.), PL-60781 Poznan, Poland; and Department of Urology, Cannizzaro Regional Hospital (F.A.), I-95126 Catania, Italy

Address all correspondence and requests for reprints to: Prof. G. G. Nussdorfer, Department of Human Anatomy and Physiology, Section of Anatomy, Via Gabelli 65, I-35121 Padova, Italy. E-mail: gastone.nusdorfer{at}unipd.it.

Cholecystokinin (CCK) IS a regulatory peptide that acts via two receptor subtypes, CCK1-R and CCK2-R. RT-PCR demonstrated the expression of both CCK1-R and CCK2-R in the zona glomerulosa (ZG), but not zona fasciculata-reticularis cells of the human adrenal cortex. CCK and the CCK2-R agonist pentagastrin enhanced basal aldosterone secretion from ZG cells without affecting cortisol production from zona fasciculata-reticularis cells. The aldosterone response to CCK and pentagastrin was suppressed by a CCK2-R antagonist, but not by a CCK1-R antagonist. Pentagastrin evoked a sizeable cAMP, but not inositol triphosphate, response from ZG cells, whereas CCK plus CCK2-R antagonist was ineffective. The cAMP response to pentagastrin was abrogated by CCK2-R antagonist or the adenylate cyclase inhibitor SQ-22536, and the aldosterone response was abolished by both SQ-22536 and the protein kinase A inhibitor H-89. Both CCK and pentagastrin increased steroidogenic acute regulatory protein mRNA expression in ZG cells; the effect was abrogated by CCK2-R antagonist. We conclude that CCK exerts secretagogue action on human ZG cells, acting through CCK2-Rs coupled to the adenylate cyclase/protein kinase A signaling cascade, which, in turn, stimulates the expression of steroidogenic acute regulatory protein, the rate-limiting step of steroidogenesis.

Abbreviations: Ang-II, Angiotensin II; CCK, cholecystokinin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IP3, inositol triphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; StAR, steroidogenic acute regulatory protein; ZF/R, zona fasciculata-reticularis; ZG, zona glomerulosa.

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