Large conductance Ca²⁺‐activated K⁺ (BK) channels promote secretagogue‐induced transition from spiking to bursting in murine anterior pituitary corticotrophs

Abstract

Key points Corticotroph cells of the anterior pituitary are electrically excitable and are an integral component of the hypothalamic‐pituitary‐adrenal axis which governs the neuroendocrine response to stress.Corticotrophs display predominantly single spike activity under basal conditions that transition to complex bursting behaviours upon stimulation by the hypothalamic secretagogues corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP); however, the underlying mechanisms controlling bursting are unknown.In this study, we show that CRH and AVP induce different patterns of corticotroph electrical activity, and we use an electrophysiological approach combined with mathematical modelling to show the ionic mechanisms for these differential effects.The data reveal that secretagogue‐induced bursting is dependent on large conductance Ca2+‐activated K+ (BK) channels and is driven primarily by CRH whereas AVP promotes an increase in single‐spike frequency through BK‐independent pathways involving activation of non‐selective cation conductances.As corticotroph excitability is differentially regulated by CRH and AVP this may allow corticotrophs to respond appropriately to different stressors. AbstractAnterior pituitary corticotroph cells are a central component of the hypothalamic‐pituitary‐adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium‐ and voltage‐activated potassium (BK) channels in spontaneous and secretagogue‐induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non‐selective conductances. Co‐stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.

Is bursting more effective than spiking in evoking pituitary hormone secretion? A spatiotemporal simulation study of calcium and granule dynamics

“…Although the absolute number of fused granules is lower when the channel and the release site are more distant, the bursting voltage trace releases more granules than the spiking trace at all time points. Thus, our simulations support the notion that adding an outward K ϩ current can, by changing spiking to bursting activity, increase secretion (6,29).…”

“…It has been argued that since hypothalamic factors act on a number of ion channels on pituitary cell membranes, electrical activity provides numerous ways for the hypothalamus to modulate pituitary hormone release. Some of these factors may even modulate the time constant of BK channels to switch the electrical activity pattern from spiking to bursting (6). The present work shows that this switch to bursting may improve the effect of hypothalamic stimulating neurohormones in increasing pituitary hormone secretion.…”

“…With regard to channel inactivation, some types of Ca 2ϩ channels are inactivated by Ca 2ϩ , (6) where gsc is the single-channel conductance. In the cluster case, the total current is simulated by summing five independent realizations of a single-channel current (Isc).…”

Heterogeneity of Calcium Responses to Secretagogues in Corticotrophs From Male Rats

“…Heterogeneity in corticotroph spontaneous electrical activity has been previously reported in both male and female mice (13, 23, 29). Interestingly, an earlier study in female rat corticotrophs identified by immunohistochemistry (30) reported spontaneous [Ca 2+ ] i activity in 65% of cells, possibly indicating the presence of sex differences in the activity of these cells.…”

Survival and growth of C57BL/6J mice lacking the BK channel,Kcnma1: lower adult body weight occurs together with higher body fat

“…; Duncan et al. ). Opening Ca V channels leads to increased cell Ca 2+ that initiates contraction of smooth muscle cells and release of vesicularly stored hormones from endocrine cells (González et al.…”