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The Journal of Neuroscience, December 15, 2000, 20(24):9290-9297

Modeling of Membrane Excitability in Gonadotropin-Releasing Hormone-Secreting Hypothalamic Neurons Regulated by Ca²⁺-Mobilizing and Adenylyl Cyclase-Coupled Receptors

Andrew P. LeBeau¹, Fredrick Van Goor², Stanko S. Stojilkovic², and Arthur Sherman¹

¹ Mathematical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and ² Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Gonadotropin-releasing hormone (GnRH) secretion from native and immortalized hypothalamic neurons is regulated by endogenous Ca²⁺-mobilizing and adenylyl cyclase (AC)-coupled receptors. Activation of both receptor types leads to an increase in action potential firing frequency and a rise in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) and neuropeptide secretion. The stimulatory action of Ca²⁺-mobilizing agonists on voltage-gated Ca²⁺ influx is determined by depletion of the intracellular Ca²⁺ pool, whereas AC agonist-stimulated Ca²⁺ influx occurs independently of stored Ca²⁺ and is controlled by cAMP, possibly through cyclic nucleotide-gated channels. Here, experimental 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-operated 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). Spontaneous electrical activity and Ca²⁺ signaling in the model are predominantly controlled by I_d, which is activated by cAMP and inhibited by high [Ca²⁺]_i. Depletion of the intracellular Ca²⁺ pool mimics the receptor-induced activation 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, increasing the activity of I_d simulates the experimental response to forskolin-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 currents that is necessary to fully account for the experimental results.

Key words: GT1 neurons; mathematical modeling; voltage-gated calcium entry; calcium-mobilization; phospholipase C; adenylyl cyclase

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20249290-08$05.00/0

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