Ca²⁺ excitability of the ER membrane: An explanation for IP₃-induced Ca²⁺ oscillations

Recent research dealing with experiments and theoretical models of Ca²⁺ excitability of the endoplasmic reticulum (ER) membrane induced by inositol 1,4,5-trisphosphate (IP₃) is reviewed. Ca²⁺ excitability refers to the ability of a small increment of cytoplasmic Ca²⁺ concentration ([Ca²⁺](i)) to trigger a large [Ca²⁺](i) pulse or oscillations. Such nonlinear regenerative behavior is conferred by the existence of IP₃ channels and Ca²⁺-ATPase transporters on the ER membrane, which extends throughout the cytoplasm. Ca²⁺ excitability resembles the plasma membrane electrical excitability of neurons and other cells: it is driven by the ionic concentration gradient across the ER membrane (higher Ca²⁺ concentration inside the ER); each [Ca²⁺](i) spike partially consumes the prestored energy that is reestablished through ATP-dependent active transport; and [Ca²⁺](i), the excitation variable, controls the nonlinear dynamic release rate of ER Ca²⁺. This review focuses on the kinetic models based on these features and on experiments dealing with the kinetic properties of [Ca²⁺](i)-dependent gating of the IP₃ receptor channel. We summarize evidence in favor of two roles for [Ca²⁺](i) in gating the channel's opening: activation at a rapid time scale and inactivation on a slower time scale. Exploiting an analogy to the well-known Hodgkin-Huxley model for neuronal electrical excitability, we show how Ca²⁺ excitability of the ER membrane can be explained by these gating properties combined with the ER Ca²⁺ pump activity. The theory's ability to predict is illustrated by comparing calculated with experimental [Ca²⁺](i) responses for pituitary gonadotrophs under various stimulus conditions.