Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress function.

Pituitary corticotroph somatostatin receptor subtype 5 signals to inhibit adrenocorticotrophin (ACTH) secretion. As ACTH deficiency results in attenuated adrenal cortisol production and an impaired stress response, we sought to clarify the role of in modifying the hypothalamic/pituitary/adrenal (HPA) axis. We generated Tg HP5 mice overexpressing duanyu1942R5 in pituitary corticotrophs that produce the ACTH precursor proopiomelanocortin (POMC). Basal ACTH and corticosterone were similar in HP5 and WT mice, while HP5 mice showed attenuated ACTH and corticosterone responses to corticotrophin releasing hormone (CRH). HP5 mice exhibited attenuated corticosterone responses upon a restraint stress test and inflammatory stress following LPS injection, as well as increased anxiety-like and depressive-like behavior on open field and forced swim tests. Pituitary corticotroph CRH receptor subtype 1 (CRHR1) mRNA expression and ACTH responses to CRH were also attenuated in HP5 mice. In AtT20 cells stably overexpressing CRHR1 expression and cAMP response to CRH were reduced, whereas both were increased after duanyu1942R5 KO. In elucidating mechanisms for these observations, we show that miR-449c suppresses both CRHR1 expression and function. We conclude that corticotroph duanyu1942R5 attenuates HPA axis responses via CRHR1 downregulation, suggesting a role for duanyu1942R5 in the pathogenesis of secondary adrenal insufficiency.

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