Generation of action potentials in a mathematical model of corticotrophs

Abstract

Corticotropin-releasing hormone (CRH) is an important regulator of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells. The intracellular signaling system that underlies this process involves modulation of voltage-sensitive Ca2+ channel activity, which leads to the generation of Ca2+ action potentials and influx of Ca2+. However, the mechanisms by which Ca2+ channel activity is modulated in corticotrophs are not currently known. We investigated this process in a Hodgkin-Huxley-type mathematical model of corticotroph plasma membrane electrical responses. We found that an increase in the L-type Ca2+ current was sufficient to generate action potentials from a previously resting state of the model. The increase in the L-type current could be elicited by either a shift in the voltage dependence of the current toward more negative potentials, or by an increase in the conductance of the current. Although either of these mechanisms is potentially responsible for the generation of action potentials, previous experimental evidence favors the former mechanism, with the magnitude of the shift required being consistent with the experimental findings. The model also shows that the T-type Ca2+ current plays a role in setting the excitability of the plasma membrane, but does not appear to contribute in a dynamic manner to action potential generation. Inhibition of a K+ conductance that is active at rest also affects the excitability of the plasma membrane.

CRH-induced Electrical Activity and Calcium Signalling in Pituitary Corticotrophs

“…There is indirect evidence suggesting that the agonist, by way of complex intracellular mechanisms, modulates the voltage sensitivity of the L-type Ca> channels embedded in the plasma membrane. We have previously constructed a Hodgkin}Huxley-type model of this process, which indicated that an increase in the L-type Ca> current is su$cient to generate repetitive action potentials (LeBeau et al (1997). Biophys.…”

<b>Localization of ATP-sensitive K</b>^<b>+</b><b> channel subunits in rat pituitary </b><b>gland </b>

“…It receives a negative feedback suppression of cortisol from the adrenal glands (Fuchsl et al, 2013). A patch-clamp experiment for membrane potential in single rat corticotrophs showed that CRH triggered a sustained [Ca 2+ ]i elevation and membrane depolarization for corticotrophs (Lee and Tse, 1997), and ACTH secretion was related to an increase in the L-type Ca 2+ current (LeBeau et al, 1997). Such an ACTH-releasing process is somehow like that of pancreatic β-cells, which release insulin through the L-type Ca 2+ channel triggered by the KATP channel (Aguilar-Bryan et al, 1995;Philipson and Fig.…”

A Hodgkin–Huxley Model Exhibiting Bursting Oscillations

“…The remaining leak current (I Leak ) represents all other ionic current contributions not specifically described. The construction of these ionic currents from electrophysiological measurements in corticotrophs has previously been described in LeBeau et al (1997) (Alberts et al, 1983, p. 335). A schematic diagram of the ionic transport processes is shown in Fig.…”

“…A Hodgkin-Huxley-type mathematical model has been constructed which includes the major plasma membrane ionic currents identified in pituitary corticotrophs and the associated intracellular Ca 2+ dynamics (LeBeau et al, 1997;Shorten et al, 1999a). In certain parameter regimes the model exhibits a novel form of bursting behaviour.…”