title: Glucocorticoids Inhibit CRH/AVP-Evoked Bursting Activity of Male Murine Anterior Pituitary Corticotrophs.
abstract: Corticotroph cells from the anterior pituitary are an integral component of the hypothalamic-pituitary-adrenal (HPA) axis, which governs the neuroendocrine response to stress. Corticotrophs are electrically excitable and fire spontaneous single-spike action potentials and also display secretagogue-induced bursting behavior. The HPA axis function is dependent on effective negative feedback in which elevated plasma glucocorticoids result in inhibition at the level of both the pituitary and the hypothalamus. In this study, we have used an electrophysiological approach coupled with mathematical modeling to investigate the regulation of spontaneous and CRH/arginine vasopressin-induced activity of corticotrophs by glucocorticoids. We reveal that pretreatment of corticotrophs with 100 nM corticosterone (CORT; 90 and 150 min) reduces spontaneous activity and prevents a transition from spiking to bursting after CRH/arginine vasopressin stimulation. In addition, previous studies have identified a role for large-conductance calcium- and voltage-activated potassium (BK) channels in the generation of secretagogue-induced bursting in corticotrophs. Using the dynamic clamp technique, we demonstrated that CRH-induced bursting can be switched to spiking by subtracting a fast BK current, whereas the addition of a fast BK current can induce bursting in CORT-treated cells. In addition, recordings from BK knockout mice (BK(-/-)) revealed that CORT can also inhibit excitability through BK-independent mechanisms to control spike frequency. Thus, we have established that glucocorticoids can modulate multiple properties of corticotroph electrical excitability through both BK-dependent and BK-independent mechanisms.
authors.affiliation: Centre for Integrative Physiology (P.J.D., M.J.S.), College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; Biomedical Neuroscience Research Group (J.T.), University of Exeter Medical School, Exeter EX4 4PL, United Kingdom; Division of Pharmacology, Toxicology, and Clinical Pharmacy (P.R.), Institute for Pharmacy, University of Tübingen, D-72076 Tübingen, Germany; and Department of Mathematics and Programs in Neuroscience and Molecular Biophysics (R.B.), Florida State University, Tallahassee, Florida 32306.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Duncan
authors.affiliation: Centre for Integrative Physiology (P.J.D., M.J.S.), College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; Biomedical Neuroscience Research Group (J.T.), University of Exeter Medical School, Exeter EX4 4PL, United Kingdom; Division of Pharmacology, Toxicology, and Clinical Pharmacy (P.R.), Institute for Pharmacy, University of Tübingen, D-72076 Tübingen, Germany; and Department of Mathematics and Programs in Neuroscience and Molecular Biophysics (R.B.), Florida State University, Tallahassee, Florida 32306.
authors.forename: Joël
authors.initials: J
authors.lastname: Tabak
authors.affiliation: Centre for Integrative Physiology (P.J.D., M.J.S.), College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; Biomedical Neuroscience Research Group (J.T.), University of Exeter Medical School, Exeter EX4 4PL, United Kingdom; Division of Pharmacology, Toxicology, and Clinical Pharmacy (P.R.), Institute for Pharmacy, University of Tübingen, D-72076 Tübingen, Germany; and Department of Mathematics and Programs in Neuroscience and Molecular Biophysics (R.B.), Florida State University, Tallahassee, Florida 32306.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.affiliation: Centre for Integrative Physiology (P.J.D., M.J.S.), College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; Biomedical Neuroscience Research Group (J.T.), University of Exeter Medical School, Exeter EX4 4PL, United Kingdom; Division of Pharmacology, Toxicology, and Clinical Pharmacy (P.R.), Institute for Pharmacy, University of Tübingen, D-72076 Tübingen, Germany; and Department of Mathematics and Programs in Neuroscience and Molecular Biophysics (R.B.), Florida State University, Tallahassee, Florida 32306.
authors.forename: Richard
authors.initials: R
authors.lastname: Bertram
authors.affiliation: Centre for Integrative Physiology (P.J.D., M.J.S.), College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; Biomedical Neuroscience Research Group (J.T.), University of Exeter Medical School, Exeter EX4 4PL, United Kingdom; Division of Pharmacology, Toxicology, and Clinical Pharmacy (P.R.), Institute for Pharmacy, University of Tübingen, D-72076 Tübingen, Germany; and Department of Mathematics and Programs in Neuroscience and Molecular Biophysics (R.B.), Florida State University, Tallahassee, Florida 32306.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shipston
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D052680:Corticotrophs / Q000187:drug effects* / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005071:Evoked Potentials / Q000187:drug effects* / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone