Local calcium uptake by SERCA into the sarcoplasmic reticulum facilitates the propagation of cytosolic calcium waves via luminal sensitization of the ryanodine receptor in cardiac myocytes.
Demonstrates a 'fire-diffuse-uptake-fire' mechanism for calcium wave propagation in cardiac myocytes, where local calcium uptake by SERCA facilitates propagation via luminal sensitization of ryanodine receptors.
Key points Cytosolic calcium (Ca 2+ ) waves result from spontaneous release of Ca 2+ from the sarcoplasmic reticulum (SR) Ca 2+ store that occurs under Ca 2+ overload conditions and can give rise to arrhythmias in the heart. The prevailing paradigm of Ca 2+ wave propagation involves cytosolic Ca 2+ ‐induced Ca 2+ release. A recent challenge to this paradigm proposed the requirement for an intra‐SR ‘sensitization’ Ca 2+ wave that primes release activation due to the luminal Ca 2+ sensitivity of the release mechanism. We tested this hypothesis in cardiac myocytes with direct simultaneous high‐resolution measurements of cytosolic and intra‐SR Ca 2+ using fluorescence confocal microscopy. We found that the increase in cytosolic Ca 2+ at the wave front preceded release and depletion of SR Ca 2+ in time, and during this latency period a transient increase of SR Ca 2+ was observed at individual release sites that gave rise to a propagating intra‐SR Ca 2+ sensitization wave. The intra‐SR sensitization wave depended on the activity of the sarco‐endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) and occurred by a mechanism where Ca 2+ uptake by SERCA at the wave front facilitates propagation of cytosolic Ca 2+ waves via luminal sensitization of the release mechanism, thus supporting a novel paradigm of a ‘fire‐diffuse‐uptake‐fire’ mechanism for Ca 2+ wave propagation. Abstract The widely accepted paradigm for cytosolic Ca 2+ wave propagation postulates a ‘fire‐diffuse‐fire’ mechanism where local Ca 2+ ‐induced Ca 2+ release (CICR) from the sarcoplasmic reticulum (SR) via ryanodine receptor (RyR) Ca 2+ release channels diffuses towards and activates neighbouring release sites, resulting in a propagating Ca 2+ wave. A recent challenge to this paradigm proposed the requirement for an intra‐SR ‘sensitization’ Ca 2+ wave that precedes the cytosolic Ca 2+ wave and primes RyRs from the luminal side to CICR. Here, we tested this hypothesis experimentally with direct simultaneous measurements of cytosolic (Ca 2+ i ; rhod‐2) and intra‐SR (Ca 2+ SR ; fluo‐5N) calcium signals during wave propagation in rabbit ventricular myocytes, using high resolution fluorescence confocal imaging. The increase in Ca 2+ i at the wave front preceded depletion of the SR at each point along the calcium wave front, while during this latency period a transient increase of Ca 2+ SR was observed. This transient elevation of Ca 2+ SR could be identified at individual release junctions and depended on the activity of the sarco‐endoplasmic reticulum Ca 2+ ‐ATPase (SERCA). Increased SERCA activity (β‐adrenergic stimulation with 1 μ m isoproterenol (isoprenaline)) decreased the latency period and increased the amplitude of the transient elevation of Ca 2+ SR , whereas inhibition of SERCA (3 μ m cyclopiazonic acid) had the opposite effect. In conclusion, the data provide experimental evidence that local Ca 2+ uptake by SERCA into the SR facilitates the propagation of cytosolic Ca 2+ waves via luminal sensitization of the RyR, and supports a novel paradigm of a ‘fire‐diffuse‐uptake‐fire’ mechanism for Ca 2+ wave propagation in cardiac myocytes.
Maxwell et al. (Tue,) reported a other. SERCA activity modulation (isoproterenol or cyclopiazonic acid) was evaluated on Cytosolic and intra-SR calcium signals during wave propagation. Local calcium uptake by SERCA into the sarcoplasmic reticulum facilitates the propagation of cytosolic calcium waves via luminal sensitization of the ryanodine receptor in cardiac myocytes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: