title: A novel mechanism of tandem activation of ryanodine receptors by cytosolic and SR luminal Ca2+during excitation-contraction coupling in atrial myocytes.
abstract: In atrial myocytes excitation-contraction coupling is strikingly different from ventricle because atrial myocytes lack a transverse tubule membrane system: Ca2+release starts in the cell periphery and propagates towards the cell centre by Ca2+-induced Ca2+release from the sarcoplasmic reticulum (SR) Ca2+store. The cytosolic Ca2+sensitivity of the ryanodine receptor (RyRs) Ca2+release channel is low and it is unclear how Ca2+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 Ca2+that we termed 'Ca2+sensitization signal'. We propose a novel paradigm of atrial ECC that is based on tandem activation of the RyRs by cytosolic and luminal Ca2+through a 'fire-diffuse-uptake-fire' (or FDUF) mechanism: Ca2+uptake by SR Ca2+pumps at the propagation front elevates Ca2+inside the SR locally, leading to luminal RyR sensitization and lowering of the cytosolic Ca2+activation threshold.
  
  
  
  In atrial myocytes Ca2+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) Ca2+store into the peripheral subsarcolemmnal junctional (j-SR) and the much more abundant central non-junctional (nj-SR) SR. Action potential (AP)-induced Ca2+entry activates Ca2+-induced Ca2+release (CICR) from j-SR ryanodine receptor (RyR) Ca2+release channels. Peripheral elevation of [Ca2+]iinitiates CICR from nj-SR and sustains propagation of CICR to the cell centre. Simultaneous confocal measurements of cytosolic ([Ca2+]i; with the fluorescent Ca2+indicator rhod-2) and intra-SR ([Ca2+]SR; fluo-5N) Ca2+in rabbit atrial myocytes revealed that Ca2+release from j-SR resulted in a cytosolic Ca2+transient of higher amplitude compared to release from nj-SR; however, the degree of depletion of j-SR [Ca2+]SRwas smaller than nj-SR [Ca2+]SR. Similarly, Ca2+signals from individual release sites of the j-SR showed a larger cytosolic amplitude (Ca2+sparks) but smaller depletion (Ca2+blinks) than release from nj-SR. During AP-induced Ca2+release the rise of [Ca2+]idetected at individual release sites of the nj-SR preceded the depletion of [Ca2+]SR, and during this latency period a transient elevation of [Ca2+]SRoccurred. We propose that Ca2+release from nj-SR is activated by cytosolic and luminal Ca2+(tandem RyR activation) via a novel 'fire-diffuse-uptake-fire' (FDUF) mechanism. This novel paradigm of atrial ECC predicts that Ca2+uptake by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) at the propagation front elevates local [Ca2+]SR, leading to luminal RyR sensitization and lowering of the activation threshold for cytosolic CICR.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Centre, Chicago, IL, 60612, USA.
authors.forename: Joshua T
authors.identifier: 0000-0001-7389-5245
authors.initials: JT
authors.lastname: Maxwell
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Centre, Chicago, IL, 60612, USA.
authors.forename: Lothar A
authors.identifier: 0000-0003-3409-8678
authors.initials: LA
authors.lastname: Blatter
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D056966:Excitation Contraction Coupling / Q000502:physiology*; D006325:Heart Atria / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: SR Ca release; atrial myocytes; excitation-contraction coupling