Sensing and refilling calcium stores in an excitable cell

Inositol 1,4,5-trisphosphate (IP₃)-induced Ca²⁺ mobilization leads to depletion of the endoplasmic reticulum (ER) and an increase in Ca²⁺ entry. We show here for the gonadotroph, an excitable endocrine cell, that sensing of ER Ca²⁺ content can occur without the Ca²⁺ release-activated Ca²⁺ current (I(crac)), but rather through the coupling of IP₃-induced Ca²⁺ oscillations to plasma membrane voltage spikes that gate Ca²⁺ entry. Thus we demonstrate that capacitative Ca² entry is accomplished through Ca²⁺- controlled Ca²⁺ entry. We develop a comprehensive model, with parameter values constrained by available experimental data, to simulate the spatiotemporal behavior of agonist-induced Ca²⁺ signals n both the cytosol and ER lumen of gonadotrophs. The model combines two previously developed models, one for ER-mediated Ca²⁺ oscillations and another for plasma membrane potential-driven Ca²⁺ oscillations. Simulations show agreement with existing experimental records of store content, cytosolic Ca²⁺ concentration ([Ca²⁺](i)), and electrical activity, and make a variety of new, experimentally testable predictions. In particular, computations with the model suggest that [Ca²⁺] in the vicinity of the plasma membrane acts as a messenger for ER content via Ca²⁺-activated K⁺ channels and Ca²⁺ pumps in the plasma membrane. We conclude that, in excitable cells that do not express I(crac), [Ca²⁺](i) profiles provide a sensitive mechanism for regulating net calcium flux through the plasma membrane during both store depletion and refilling.