Facilitation of cytosolic calcium wave propagation by local calcium uptake into the sarcoplasmic reticulum in cardiac myocytes
Article first published online: 15 OCT 2012
© 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society
The Journal of Physiology
Volume 590, Issue 23, pages 6037–6045, December 2012
How to Cite
Maxwell, J. T. and Blatter, L. A. (2012), Facilitation of cytosolic calcium wave propagation by local calcium uptake into the sarcoplasmic reticulum in cardiac myocytes. The Journal of Physiology, 590: 6037–6045. doi: 10.1113/jphysiol.2012.239434
- Issue published online: 28 NOV 2012
- Article first published online: 15 OCT 2012
- (Received 20 June 2012; accepted after revision 16 September 2012; first published online 17 September 2012)
- • Cytosolic calcium (Ca2+) waves result from spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR) Ca2+ store that occurs under Ca2+ overload conditions and can give rise to arrhythmias in the heart. The prevailing paradigm of Ca2+ wave propagation involves cytosolic Ca2+-induced Ca2+ release.
- • A recent challenge to this paradigm proposed the requirement for an intra-SR ‘sensitization’ Ca2+ wave that primes release activation due to the luminal Ca2+ sensitivity of the release mechanism.
- • We tested this hypothesis in cardiac myocytes with direct simultaneous high-resolution measurements of cytosolic and intra-SR Ca2+ using fluorescence confocal microscopy.
- • We found that the increase in cytosolic Ca2+ at the wave front preceded release and depletion of SR Ca2+ in time, and during this latency period a transient increase of SR Ca2+ was observed at individual release sites that gave rise to a propagating intra-SR Ca2+ sensitization wave.
- • The intra-SR sensitization wave depended on the activity of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) and occurred by a mechanism where Ca2+ uptake by SERCA at the wave front facilitates propagation of cytosolic Ca2+ waves via luminal sensitization of the release mechanism, thus supporting a novel paradigm of a ‘fire-diffuse-uptake-fire’ mechanism for Ca2+ wave propagation.
Abstract The widely accepted paradigm for cytosolic Ca2+ wave propagation postulates a ‘fire-diffuse-fire’ mechanism where local Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) via ryanodine receptor (RyR) Ca2+ release channels diffuses towards and activates neighbouring release sites, resulting in a propagating Ca2+ wave. A recent challenge to this paradigm proposed the requirement for an intra-SR ‘sensitization’ Ca2+ wave that precedes the cytosolic Ca2+ wave and primes RyRs from the luminal side to CICR. Here, we tested this hypothesis experimentally with direct simultaneous measurements of cytosolic ([Ca2+]i; rhod-2) and intra-SR ([Ca2+]SR; fluo-5N) calcium signals during wave propagation in rabbit ventricular myocytes, using high resolution fluorescence confocal imaging. The increase in [Ca2+]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 [Ca2+]SR was observed. This transient elevation of [Ca2+]SR could be identified at individual release junctions and depended on the activity of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA). Increased SERCA activity (β-adrenergic stimulation with 1 μm isoproterenol (isoprenaline)) decreased the latency period and increased the amplitude of the transient elevation of [Ca2+]SR, whereas inhibition of SERCA (3 μm cyclopiazonic acid) had the opposite effect. In conclusion, the data provide experimental evidence that local Ca2+ uptake by SERCA into the SR facilitates the propagation of cytosolic Ca2+ waves via luminal sensitization of the RyR, and supports a novel paradigm of a ‘fire-diffuse-uptake-fire’ mechanism for Ca2+ wave propagation in cardiac myocytes.