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(+)/Ca(2+) exchanger (NCX), a process which is essential for reloading the sarcoplasmic reticulum (SR) via the sarco/endoplasmic reticulum Ca(2+)ATPase (SERCA) and maintaining Ca(2+) oscillations in activated vascular smooth muscle. Having previously modeled the flow of Ca(2+) 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 Ca(2+) influx to refill the SR.
Fameli
Nicola
N
Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada. fameli@interchange.ubc.ca
Kuo
Kuo-Hsing
KH
van Breemen
Cornelis
C
D000818:Animals; D020013:Calcium Signaling; D003198:Computer Simulation; D017136:Ion Transport; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D050052:TRPC Cation Channels / Q000378:metabolism*
D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases