A model for the generation of localized transient [Na+] elevations in vascular smooth muscle

We present a stochastic computational model to study the mechanism of signaling between a source and a target ionic transporter, both localized on the plasma membrane (PM). In general this requires a nanometer-scale cytoplasmic space, or nanodomain, between the PM and a peripheral organelle to reflect ions back towards the PM. Specifically we investigate the coupling between Na+ entry via the transient receptor potential canonical channel 6 (TRPC6) and the Na+/Ca2+ exchanger (NCX), a process which is essential for reloading the sarcoplasmic reticulum (SR) via the sarco/endoplasmic reticulum Ca2+ATPase (SERCA) and maintaining Ca2+ oscillations in activated vascular smooth muscle. Having previously modeled the flow of Ca2+ between reverse NCX and SERCA during SR refilling, this quantitative approach now allows us to model the upstream linkage of Na+ entry through TRPC6 to reversal of NCX. We have implemented a random walk (RW) Monte Carlo (MC) model with simulations mimicking a diffusion process originating at the TRPC6 within PM–SR junctions. The model calculates the average Na+ in the nanospace and also produces profiles as a function of distance from the source. Our results highlight the necessity of a strategic juxtaposition of the relevant ion translocators as well as other physical structures within the nanospaces to permit adequate Na+ build-up to initiate NCX reversal and Ca2+ influx to refill the SR.