Subcellular Ca Channel Distribution and Ca Alternans in Atrial Myocytes

Abstract

Unlike ventricular myocytes, atrial myocytes have a much less well-developed T-tubular network, especially in rodents. In this study, we carried out computer simulations to investigate the consequences of a T tubular network on the development of spatially discordant Ca alternans in atrial myocytes. Our study was motivated by experimental observations in isolated mouse atrial myocytes, which express both Cav1.2 and Cav1.3 channels. Knocking out Cav1.3, but not Cav1.2, promoted spatially discordant Ca alternans in which Ca amplitude alternates out-of-phase in different regions of the myocyte. Based on observations in sinoatrial myocytes that Cav1.2 channels are mainly distributed on the surface of the cell while Cav1.3 channels are more uniformly distributed throughout the whole cell, in our computer model, we coupled both types of channels to Ca release units on the surface of the cell, but only Cav1.3 to Ca release units in the interior of the cell. The cell model was paced with a clamped voltage waveform at a pacing cycle length of 300 msec. Under control, Ca transient was normal, and no alternans were observed. When Cav1.2 channels were removed, the Ca transient amplitude decreased, but alternans did not occur. When Cav1.3 channels were removed, however, Ca alternans occurred. The magnitude of the whole-cell Ca transient alternans varied over time, exhibiting a modulated pattern. The line scan showed spatially discordant alternans. These simulations show that the subcellular distribution of Ca channels in relation to Ca release units has important effects on the proclivity for spatially discordant Ca alternans. Specifically, a high fraction of orphaned RyR clusters in the center of the myocyte facilitates spatially discordant Ca alternans.