CATION CONDUCTION IN THE CALCIUM-RELEASE CHANNEL OF THE CARDIAC SARCOPLASMIC-RETICULUM UNDER PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL CONDITIONS

Objective: The aim was to perform a theoretical and experimental study of the possible variations in Ca2+ current through the open cardiac sarcoplasmic reticular Ca2+ release channel under the ionic conditions associated with physiological and pathophysiological states. Methods: The sheep cardiac sarcoplasmic reticular Ca2+ release channel was purified and reconstituted into planar phospholipid bilayers for study under voltage clamp conditions. Single channel current-voltage relationships were measured under putative physiological conditions with 1, 5, and 10 mM intraluminal Ca2+. The mathematics of a computer model based on Eyring rate theory were extended to include the interactions of three permeant ions. Results: A model used previously to describe ionic conduction under simpler ionic conditions was able to predict the interaction of Ca2+, Mg2+, and K+ in the probable physiological range over the voltage range of interest. The predicted Ca2+ current under ionic conditions proposed to occur at the end of diastole is sensitive to relatively small changes in holding potential which suggests the need for adequate charge compensation across the sarcoplasmic reticular membrane. Theoretically, it was predicted that variations in intraluminal Ca2+, such as may occur in Ca2+ overload and other conditions, and variations in cytosolic Mg2+, which may occur in myocardial stunning, may significantly affect Ca2+ flux through the open Ca2+ release channel. Conclusions: Variations in permeant ion concentration such as may occur in physiological and pathophysiological states may significantly affect the quantity of Ca2+ released from the cardiac sarcoplasmic reticulum.