Distribution And Clustering Of Membrane Ca2+ Transporters Regulate Ca2+ Signals In Rat Ventricular Myocytes

In ventricular cardiac cells, the t-tubule microanatomy and the distribution and clustering of membrane Ca2+ transporters (L-type Ca2+ channel, Na+/Ca2+ exchanger, sarcolemmal Ca2+ ATPase) are considered important in Ca2+ regulation [1]. Their variations over time may hold clues to the progression of heart diseases [1,2]. To examine how these sub-cellular mechanisms regulate the Ca2+ signals in rat myocytes with inhibited sarcoplasmic reticulum we used modeling approach [3]. The t-tubule geometry was derived from light microscopy images and Ca2+ diffusion and buffering by stationary and mobile Ca2+ buffers (troponin C, ATP, calmodulin, Fluo-3) were taken into account [3,4]. In agreement with experiment: (1) the L-type Ca2+ current density was higher along the t-tubule, the spacing between adjacent L-type Ca2+ clusters was assumed ∼0.68 μm, and the average L-type Ca2+ cluster size was ∼50 nm in radius [2,5]; (2) the Na+/Ca2+ current density was higher and uniform along the t-tubule and Na+/Ca2+ exchanger was located within (or close to) L-type Ca2+ clusters [1]; (3) the sarcolemmal Ca2+ pump was uniformly distributed along the sarcolemma co-localizing or not with L-type Ca2+ clusters. The results indicate that spatial Ca2+ signals critically depend on the local diffusion properties and the location and clustering of Ca2+ transporters along the cell membrane. [1] Isuru et al., Biophy J 97:2664-2673, 2009. [2] Ye Chen-Izu et al, Biophys J 91:1-13 2006. [3] Cheng et al., PLoS Comp Biol 2010, (in press). [4] Hayashi et al., J Cell Science 122:1005-1013, 2009. [5] Gathercole et al., J Mol Cell Cardiol 32:1981-1994, 2000. Supported by NBCR (NIH grant 5P41 RR08605-16).