Finite element analysis predicts Ca(2+) microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle

A finite element analysis modelled diffusional generation of steady-state Ca(2+) microdomains within skeletal muscle transverse (T)-tubular-sarcoplasmic reticular (SR) junctions, sites of ryanodine receptor (RyR)-mediated SR Ca(2+) release. It used established quantifications of sarcomere and T-SR anatomy (radial diameter [Formula: see text] ; axial distance [Formula: see text] ). Its boundary SR Ca(2+) influx densities,[Formula: see text] , reflected step impositions of influxes, [Formula: see text] deduced from previously measured Ca(2+) signals following muscle fibre depolarization. Predicted steady-state T-SR junctional edge [Ca(2+)], [Ca(2+)](edge,) matched reported corresponding experimental cytosolic [Ca(2+)] elevations given diffusional boundary efflux [Formula: see text] established cytosolic Ca(2+) diffusion coefficients [Formula: see text] and exit length [Formula: see text] . Dependences of predicted [Ca(2+)](edge) upon [Formula: see text] then matched those of experimental [Ca(2+)] upon Ca(2+) release through their entire test voltage range. The resulting model consistently predicted elevated steady-state T-SR junctional ~ µM-[Ca(2+)] elevations radially declining from maxima at the T-SR junction centre along the entire axial T-SR distance. These [Ca(2+)] heterogeneities persisted through 10(4)- and fivefold, variations in D and w around, and fivefold reductions in d below, control values, and through reported resting muscle cytosolic [Ca(2+)] values, whilst preserving the flux conservation ([Formula: see text] condition, [Formula: see text] . Skeletal muscle thus potentially forms physiologically significant ~ µM-[Ca(2+)] T-SR microdomains that could regulate cytosolic and membrane signalling molecules including calmodulin and RyR, These findings directly fulfil recent experimental predictions invoking such Ca(2+) microdomains in observed regulatory effects upon Na(+) channel function, in a mechanism potentially occurring in similar restricted intracellular spaces in other cell types.