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1 Department of Physiology, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland
In heart muscle the amplification and shaping of Ca2+ signals governing contraction are orchestrated by recruiting a variable number of Ca2+ sparks. Sparks reflect Ca2+ release from the sarcoplasmic reticulum (SR) via Ca2+ release channels (ryanodine receptors, RyRs). RyRs are activated by Ca2+ influx via L-type Ca2+ channels with a specific probability that may depend on regulatory mechanisms (e.g. ß-adrenergic stimulation) or diseased states (e.g. heart failure). Changes of RyR phosphorylation may be critical for both regulation and impaired function in disease. Using UV flash photolysis of caged Ca2+ and short applications of caffeine in guinea-pig ventricular myocytes, we found that Ca2+ release signals on the cellular level were largely governed by global SR content. During ß-adrenergic stimulation resting myocytes exhibited smaller SR Ca2+ release signals when activated by photolysis (62.3% of control), resulting from reduced SR Ca2+ content under these conditions (58.6% of control). In contrast, local signals triggered with diffraction limited two-photon photolysis displayed the opposite behaviour, exhibiting a larger Ca2+ release (164% of control) despite reduced global and local SR Ca2+ content. This apparent paradox implies changes of RyR open probabilities after ß-adrenergic stimulation, enhancing local regenerativity and reliability of Ca2+ signalling. Thus, our results underscore the importance of phosphorylation of RyRs (or of a related protein), as a regulatory physiological mechanism that may also provide new therapeutic avenues to recover impaired Ca2+ signalling during cardiac disease.
(Received 2 February 2005;
accepted after revision 3 March 2005;
first published online 17 March 2005)
Corresponding author E. Niggli: Department of Physiology, University of Bern, 3012 Bern, Switzerland. Email: niggli{at}pyl.unibe.ch
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