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

Biochem Biophys Res Commun. 2009 Nov 20;389(3):461-5. doi: 10.1016/j.bbrc.2009.08.166. Epub 2009 Sep 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Computer Simulation*
  • Ion Transport
  • Models, Biological*
  • Muscle, Smooth, Vascular / metabolism*
  • Rabbits
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Sodium / metabolism*
  • Sodium-Calcium Exchanger / metabolism
  • TRPC Cation Channels / metabolism*

Substances

  • Sodium-Calcium Exchanger
  • TRPC Cation Channels
  • Sodium
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases