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

Area of Science:

• Endocrinology
• Neuroscience
• Molecular Biology

Background:

• Pituitary somatostatin receptor subtype 5 (SSTR5) inhibits adrenocorticotrophin (ACTH) secretion.
• ACTH deficiency impairs adrenal cortisol production and the stress response.
• The role of SSTR5 in modulating the hypothalamic/pituitary/adrenal (HPA) axis requires clarification.

Purpose of the Study:

• To investigate the function of SSTR5 in regulating the HPA axis and stress responses.
• To determine the molecular mechanisms by which SSTR5 influences ACTH secretion and CRH signaling.

Main Methods:

• Generation of transgenic HP5 mice overexpressing SSTR5 in pituitary corticotrophs.
• Assessment of ACTH and corticosterone levels under basal and stress conditions (CRH stimulation, restraint stress, LPS injection).
• Behavioral tests (open field, forced swim) to evaluate anxiety- and depressive-like behaviors.
• Analysis of CRH receptor subtype 1 (CRHR1) expression and function in mouse pituitary and AtT20 cells.
• Investigation of the role of miR-449c in mediating SSTR5 effects on CRHR1.

Main Results:

• HP5 mice exhibited attenuated ACTH and corticosterone responses to CRH, restraint stress, and LPS.
• HP5 mice displayed increased anxiety- and depressive-like behaviors.
• SSTR5 overexpression reduced pituitary CRHR1 mRNA expression and ACTH responses to CRH.
• SSTR5-induced miR-449c was identified as a suppressor of CRHR1 expression and function.

Conclusions:

• Corticotroph SSTR5 attenuates HPA axis responses by downregulating CRHR1 expression and function.
• SSTR5 plays a significant role in regulating the HPA axis and stress adaptation.
• Dysregulation of SSTR5 may contribute to the pathogenesis of secondary adrenal insufficiency.