Modeling of membrane excitability in gonadotropin-releasing hormone-secreting hypothalamic neurons regulated by Ca2+ mobilizing and adenylyl cyclase-coupled receptors

Gonadotropin-releasing hormone (GnRH) secretion from native and immortalize d hypothalamic neurons is regulated by endogenous Ca2+-mobilizing and adeny lyl cyclase (AC)-coupled receptors. Activation of both receptor types leads to an increase in action potential firing frequency and a rise in the intr acellular Ca2+ concentration ([Ca2+](i)) and neuropeptide secretion. The st imulatory action of Ca2+-mobilizing agonists on voltage-gated Ca2+ influx i s determined by depletion of the intracellular Ca2+ pool, whereas AC agonis t-stimulated Ca2+ influx occurs independently of stored Ca2+ and is control led by cAMP, possibly through cyclic nucleotide-gated channels. Here, exper imental records from immortalized GnRH-secreting neurons are simulated with a mathematical model to determine the requirements for generating complex membrane potential (V-m) and [Ca2+](i) responses to Ca2+-mobilizing and AC agonists. Included in the model are three pacemaker currents: a store-opera ted Ca2+ current (I-SOC), an SK-type Ca2+-activated K+ current (I-SK), and an inward current that is modulated by cAMP and [Ca2+](i) (I-d). Spontaneou s electrical activity and Ca2+ signaling in the model are predominantly con trolled by I-d, which is activated by cAMP and inhibited by high [Ca2+](i). Depletion of the intracellular Ca2+ pool mimics the receptor-induced activ ation of I-SOC and I-SK, leading to an increase in the firing frequency and Ca2+ influx after a transient cessation of electrical activity. However, i ncreasing the activity of I-d simulates the experimental response to forsko lin- induced activation of AC. Analysis of the behaviors of I-SOC, I-d, and I-SK in the model reveals the complexity in the interplay of these current s that is necessary to fully account for the experimental results.