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

KEY POINTS

In atrial myocytes excitation-contraction coupling is strikingly different from ventricle because atrial myocytes lack a transverse tubule membrane system: Ca release starts in the cell periphery and propagates towards the cell centre by Ca -induced Ca release from the sarcoplasmic reticulum (SR) Ca store. The cytosolic Ca sensitivity of the ryanodine receptor (RyRs) Ca release channel is low and it is unclear how Ca release can be activated in the interior of atrial cells. Simultaneous confocal imaging of cytosolic and intra-SR calcium revealed a transient elevation of store Ca that we termed 'Ca sensitization signal'. We propose a novel paradigm of atrial ECC that is based on tandem activation of the RyRs by cytosolic and luminal Ca through a 'fire-diffuse-uptake-fire' (or FDUF) mechanism: Ca uptake by SR Ca pumps at the propagation front elevates Ca inside the SR locally, leading to luminal RyR sensitization and lowering of the cytosolic Ca activation threshold.

ABSTRACT

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 ] initiates CICR from nj-SR and sustains propagation of CICR to the cell centre. Simultaneous confocal measurements of cytosolic ([Ca ] ; with the fluorescent Ca indicator rhod-2) and intra-SR ([Ca ] ; fluo-5N) 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 ] was smaller than nj-SR [Ca ] . 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 ] detected at individual release sites of the nj-SR preceded the depletion of [Ca ] , and during this latency period a transient elevation of [Ca ] 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 sarco-endoplasmic reticulum Ca -ATPase (SERCA) at the propagation front elevates local [Ca ] , leading to luminal RyR sensitization and lowering of the activation threshold for cytosolic CICR.