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Hypothalamic-Pituitary-Adrenal Axis Hyporesponsiveness to Restraint Stress in Mice Deficient for Large-Conductance Calcium- and Voltage-Activated Potassium (BK) Channels

Centre for Integrative Physiology (P.J.B., J.A.R., M.J.S.), School of Biomedical Science, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom; Pharmacology and Toxicology (M.S., U.S., P.R.), University Tübingen, Institute of Pharmacy, 72076 Tübingen, Germany; and Division of Molecular and Cellular Pharmacology (G.W., H.-G.K.), Medical University Innsbruck, Innsbruck A-6020, Austria

Address all correspondence and requests for reprints to: Michael J. Shipston, Centre for Integrative Physiology, School of Biomedical Science, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom. E-mail: mike.shipston{at}ed.ac.uk.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing ACTH from the anterior pituitary gland and glucocorticoids from the adrenal cortex. Stress also activates the sympathetic nervous system, evoking adrenaline release from the adrenal medulla. Large-conductance calcium- and voltage-activated potassium (BK) channels have been implicated in regulation of cellular excitability in these systems. Here, we examine the functional role of BK channels in HPA axis regulation in vivo using female mice genetically deficient (BK^–/–) for the pore-forming subunits of BK channels. BK^–/– phenotype in the HPA was confirmed by immunohistochemistry, Western blot analysis, and corticotrope patch-clamp recording. Restraint stress-induced plasma concentrations of ACTH and corticosterone were significantly blunted in BK^–/– mice compared with wild type (WT) controls. This stress hyporesponsiveness was associated with reduced activation of hypothalamic paraventricular nucleus (PVN) neurons. Basal expression of CRH, but not arginine vasopressin mRNA in the PVN was significantly lower in BK^–/– mice compared with WT controls. Total anterior pituitary ACTH peptide content, but not proopiomelanocortin mRNA expression or corticotrope number, was significantly reduced in BK^–/– mice compared with WT. However, anterior pituitary corticotropes from BK^–/– mice fully supported ACTH output, releasing a significantly greater proportion of stored ACTH in response to secretagogue in vitro compared with WT. These results support an important role for BK channels in both the neural circuitry and endocrine output of the HPA axis and indicate that the stress hyporesponsiveness in BK^–/– mice primarily results from reduced activation of hypothalamic PVN neurosecretory neurons.