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...

The endocrine cells of the anterior pituitary gland are electrically active when stimulated or, in some cases, when not inhibited. The activity pattern thought to be most effective in releasing hormones is bursting, which consists of depolarization with small spikes that are much longer than single spikes. Although a majority of the research on cellular activity patterns has been performed on dispersed cells, the environment in situ is characterized by networks of coupled cells of the same type, at least in the case of somatotrophs and lactotrophs. This produces some degree of synchronization of their activity, which can be greatly increased by hormones and changes in the physiological state. In this computational study, we examine how electrical coupling among model cells influences synchronization of bursting oscillations among the population. We focus primarily on weak electrical coupling, since strong coupling leads to complete synchronization that is not characteristic of pituitary cell networks. We first look at small networks to point out several unexpected behaviors of the coupled system, and then consider a larger random scale-free network to determine what features of the structural network formed through gap junctional coupling among cells produce a high degree of functional coupling, i.e., clusters of synchronized cells. We employ several network centrality measures, and find that cells that are closely related in terms of their closeness centrality are most likely to be synchronized. We also find that structural hubs (cells with extensive coupling to other cells) are typically not functional hubs (cells synchronized with many other cells). Overall, in the case of weak electrical coupling, it is hard to predict the functional network that arises from a structural network, or to use a functional network as a means for determining the structural network that gives rise to it.

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Electrical bursting oscillations in neurons and endocrine cells are activity patterns that facilitate the secretion of neurotransmitters and hormones and have been the focus of study for several decades. Mathematical modeling has been an extremely useful tool in this effort, and the use of fast-slow analysis has made it possible to understand bursting from a dynamic perspective and to make testable predictions about changes in system parameters or the cellular environment. It is typically the case that the electrical impulses that occur during the active phase of a burst are due to stable limit cycles in the fast subsystem of equations or, in the case of so-called “pseudo-plateau bursting,” canards that are induced by a folded node singularity. In this article, we show an entirely different mechanism for bursting that relies on stochastic opening and closing of a key ion channel. We demonstrate, using fast-slow analysis, how the short-lived stochastic channel openings can yield a much longer response in which single action potentials are converted into bursts of action potentials. Without this stochastic element, the system is incapable of bursting. This mechanism can describe stochastic bursting in pituitary corticotrophs, which are small cells that exhibit a great deal of noise as well as other pituitary cells, such as lactotrophs and somatotrophs that exhibit noisy bursts of electrical activity.