Chronic stress facilitates bursting electrical activity in pituitary corticotrophs

Abstract

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‐ and voltage‐activated (BK) potassium channels that are critical for promoting corticotrophin‐releasing hormone (CRH)‐induced bursting that enhances adrenocorticotrophic hormone secretion. Previous studies revealed hypothalamic–pituitary–adrenal 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‐dependent 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‐type Ca2+ channels determines bursting activity. Surprisingly, CS corticotrophs (but not unstressed) display CRH‐induced 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‐type Ca2+ channels. Our data reveal that changes in the stochastic behaviour of a small number of BK channels can finely tune corticotroph excitability through stress‐induced 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‐expressing endocrine cells, with important implications for the physiological processes they regulate and the potential for therapy. Key points Chronic stress (CS) is predicted to modify the electrical excitability of anterior pituitary corticotrophs. Electrophysiological recordings from isolated corticotrophs from CS male mice display spontaneous electrical bursting behaviour compared to the tonic spiking behaviour of unstressed corticotrophs. The increased spontaneous bursting from CS corticotrophs is BK‐dependent and mathematical modelling reveals that the time constant of activation, properties and proportion of BK channels functionally coupled to L‐type calcium channels determines the promotion of bursting activity. CS (but not unstressed) corticotrophs display corticotrophin‐releasing hormone‐induced 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. Corticotroph excitability can be finely tuned by the stochastic behaviour of a small number of BK channels dependent on their properties and functional co‐localisation with L‐type calcium channels to control corticotroph excitability over diverse time domains an...

Network Properties of Electrically Coupled Bursting Pituitary Cells

“…In gonadotrophs, long “plateau bursts” are produced when the cells are activated through the release of Ca 2+ from intracellular stores and its action on Ca 2+ -activated K + channels ( 5 ). In the other cell types, shorter “pseudo-plateau bursts” are produced by ionic current through plasma membrane ion channels and feedback from intracellular Ca 2+ onto SK– and BK–type K + channels ( 1 , 6 – 8 ).…”

Glucocorticoid action in the anterior pituitary gland: Insights from corticotroph physiology

“…Using a 2-week chronic stress model in Pomc-GFP mice, corticotroph spontaneous and CRH-induced excitability is significantly elevated in part dependent on enhanced pseudo-plateau bursting. This bursting is due to functional BK channels [ 75 ], supporting the hypothesis that chronic stress results in intrinsic changes in membrane excitability. Whether this enhanced excitability is a direct result of glucocorticoid signalling at the pituitary corticotroph per se , or whether corticotroph excitability is suppressed during recovery from the chronic stress, is not known.…”

Sex differences in pituitary corticotroph excitability

“…Of these 71 ion channel genes, 44 were enriched in males and 27 enriched in females, as shown in the heatmap for each independent experiment ( Figure 8C ). Differentially expressed ion channel genes spanned multiple families from the cation and anion families, including multiple voltage-gated pore-forming and accessory subunits that are likely the molecular basis of core components of ionic conductances regulating corticotroph excitability ( Liang et al, 2011 ; Duncan et al, 2015 ; Duncan et al, 2022 ). Intriguingly, the expression of the single gene encoding the pore-forming subunit BK channels ( Kcnma1 ) and its regulatory γ-subunit ( Lrrc52 ) were significantly ( p < 0.01) lower in female corticotrophs (2.0- and 5.8-fold lower, respectively) than those in males.…”

“…Thus, a lack of BK channels per se is unlikely to explain the lack of bursting in these cells. Indeed, only a small number of BK channels co-localized with calcium channels are required for CRH-dependent bursting ( Duncan et al, 2022 ), and “rescue” of CRH-bursting in male corticotrophs exposed to glucocorticoids can be achieved by the introduction of BK conductance using a dynamic clamp ( Duncan et al, 2016 ). Thus, it is likely that the ion channel landscape in A-type corticotrophs and coupling to CRH-dependent signaling pathways are distinct from those in B-type corticotrophs in both sexes.…”