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 Ca(2+)-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.