A novel mechanism of tandem activation of ryanodine receptors by cytosolic and SR luminal Ca during excitation-contraction coupling in atrial myocytes

In atrial myocytes Ca release during excitation-contraction coupling (ECC) is strikingly different from ventricular myocytes. In many species atrial myocytes lack a transverse tubule system, dividing the sarcoplasmic reticulum (SR) Ca store into the peripheral subsarcolemmnal junctional (j-SR) and the much more abundant central non-junctional (nj-SR) SR. Action potential (AP)-induced Ca entry activates Ca-induced Ca release (CICR) from j-SR ryanodine receptor (RyR) Ca release channels. Peripheral elevation of [Ca]_i initiates CICR from nj-SR and sustains propagation of CICR to the cell centre. Simultaneous confocal measurements of cytosolic ([Ca]_i; with the fluorescent Ca indicator rhod-2) and intra-SR ([Ca]_SR; fluo-5 N) Ca in rabbit atrial myocytes revealed that Ca release from j-SR resulted in a cytosolic Ca transient of higher amplitude compared to release from nj-SR, however the degree of depletion of j-SR [Ca]_SR was smaller than nj-SR [Ca]_SR. Similarly, Ca signals from individual release sites of the j-SR showed a larger cytosolic amplitude (Ca sparks) but smaller depletion (Ca blinks) than release from nj-SR. During AP-induced Ca release the rise of [Ca]_i detected at individual release sites of the nj-SR preceded the depletion of [Ca]_SR, and during this latency period a transient elevation of [Ca]_SR occurred. We propose that Ca release from nj-SR is activated by cytosolic and luminal Ca (tandem RyR activation) via a novel 'fire-diffuse-uptake-fire' (FDUF) mechanism. This novel paradigm of atrial ECC predicts that Ca uptake by SERCA at the propagation front elevates local [Ca]_SR, leading to luminal RyR sensitization and lowering of the activation threshold for cytosolic CICR.

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