BK channels have opposite effects on sodium versus calcium-mediated action potentials in endocrine pituitary cells

Pituitary endocrine cells fire action potentials (APs) to regulate their cytosolic Ca 2+ concentration and hormone secretion rate. Depending on animal species, cell type, and biological conditions, pituitary APs are generated either by TTX-sensitive Na + currents ( I Na ), high-voltage activated Ca 2+ currents ( I Ca ), or by a combination of the two. Previous computational models of pituitary cells have mainly been based on data from rats, where I Na is largely inactivated at the resting potential, and spontaneous APs are exclusively mediated by I Ca . As a part of the previous modeling studies, a paradoxical role was identified for the big conductance K + current ( I BK ), which was found to prolong the duration of I Ca -mediated APs, and sometimes give rise to pseudo-plateau bursts, contrary to what one would expect from a hyperpolarizing current. Unlike in rats, spontaneous I Na -mediated APs are consistently seen in pituitary cells of several other animal species, including several species of fish. In the current work we develop the, to our knowledge, first computational model of a pituitary cell that fires I Na -mediated APs. Although we constrain the model to experimental data from gonadotrope cells in the teleost fish medaka ( Oryzias latipes ), it may likely provide insights also into other pituitary cell types that fire I Na -mediated APs. In the current work, we use the model to explore how the effect of I BK depends on the AP generating mechanisms of pituitary cells. We do this by comparing simulations on the medaka gonadotrope model (two versions thereof) with simulations on a previously developed model of a rat pituitary cell. Interestingly, we find that I BK has the opposite effect on APs in the two models, i.e. it reduces the duration of already fast I Na -mediated APs in the medaka model, and prolongs the duration of already slow I Ca -mediated APs in the rat model. Author summary Excitable cells elicit electrical pulses called action potentials (APs), which are generated and shaped by a combination of ion channels in the cell membrane. While neurons use APs for interneuronal communication and heart cells use them to generate heart-beats, pituitary cells use APs to regulate their cytosolic Ca 2+ concentration, which in turn controls their hormone secretion rate. The amount of Ca 2+ that enters the pituitary cell during an AP depends strongly on how long it lasts, and it is therefore important to understand the mechanisms that control this. Depending on animal species and biological conditions, pituitary APs may be initiated either by Ca 2+ channels or Na + channels. Here, we explore the differences between the two scenarios by comparing simulations on two different computer models: (i) a previously developed model which fires Na + -based APs, adapted to data from pituitary cells in rats, and (ii) a novel model that fires Ca 2+ -based APs, adapted to data from pituitary cells in the fish medaka. Interestingly, we find that the role of big conductance K + (BK) channels, which are known to affect the duration of the AP, are opposite in the two models, i.e., they act to prolong Ca 2+ -based APs while they act to shorten Na + -based APs.