{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T08:18:54Z","timestamp":1778573934869,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Coordination of an appropriate stress response is dependent upon anterior pituitary corticotroph excitability in response to hypothalamic secretagogues and glucocorticoid negative feedback. A key determinant of corticotroph excitability is large conductance calcium\u2010 and voltage\u2010activated (BK) potassium channels that are critical for promoting corticotrophin\u2010releasing hormone (CRH)\u2010induced bursting that enhances adrenocorticotrophic hormone secretion. Previous studies revealed hypothalamic\u2013pituitary\u2013adrenal axis hyperexcitability following chronic stress (CS) is partly a function of increased corticotroph output. Thus, we hypothesise that chronic stress promotes corticotroph excitability through a BK\u2010dependent mechanism. Corticotrophs from CS mice displayed significant increase in spontaneous bursting, which was suppressed by the BK blocker paxilline. Mathematical modelling reveals that the time constant of BK channel activation, plus properties and proportion of BK channels functionally coupled to L\u2010type Ca<jats:sup>2+<\/jats:sup> channels determines bursting activity. Surprisingly, CS corticotrophs (but not unstressed) display CRH\u2010induced bursting even when the majority of BK channels are inhibited by paxilline, which modelling suggests is a consequence of the stochastic behaviour of a small number of BK channels coupled to L\u2010type Ca<jats:sup>2+<\/jats:sup> channels. Our data reveal that changes in the stochastic behaviour of a small number of BK channels can finely tune corticotroph excitability through stress\u2010induced changes in BK channel properties. Importantly, regulation of BK channel function is highly context dependent allowing dynamic control of corticotroph excitability over a large range of time domains and physiological challenges in health and disease. This is likely to occur in other BK\u2010expressing endocrine cells, with important implications for the physiological processes they regulate and the potential for therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Chronic stress (CS) is predicted to modify the electrical excitability of anterior pituitary corticotrophs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Electrophysiological recordings from isolated corticotrophs from CS male mice display spontaneous electrical bursting behaviour compared to the tonic spiking behaviour of unstressed corticotrophs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The increased spontaneous bursting from CS corticotrophs is BK\u2010dependent and mathematical modelling reveals that the time constant of activation, properties and proportion of BK channels functionally coupled to L\u2010type calcium channels determines the promotion of bursting activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CS (but not unstressed) corticotrophs display corticotrophin\u2010releasing hormone\u2010induced bursting even when the majority of BK channels are pharmacologically inhibited, which can be explained by the stochastic behaviour of a small number of BK channels with distinct properties.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Corticotroph excitability can be finely tuned by the stochastic behaviour of a small number of BK channels dependent on their properties and functional co\u2010localisation with L\u2010type calcium channels to control corticotroph excitability over diverse time domains and physiological challenges.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282367","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T16:25:27Z","timestamp":1638462327000},"page":"313-332","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chronic stress facilitates bursting electrical activity in pituitary corticotrophs"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5201-6272","authenticated-orcid":false,"given":"Peter J.","family":"Duncan","sequence":"first","affiliation":[{"name":"Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh 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