Ryanodine receptor current amplitude controls Ca2+ sparks in cardiac muscle.
BACKGROUND
In cardiac muscle, Ca(2+)-induced Ca(2+) release (CICR) from the sarcoplasmic reticulum (SR) is mediated by ryanodine receptor (RyR) Ca(2+) release channels. The inherent positive feedback of CICR is normally well-controlled. Understanding this control mechanism is a priority because its malfunction has life-threatening consequences.


OBJECTIVE
We show that CICR local control is governed by SR Ca(2+) load, largely because load determines the single RyR current amplitude that drives inter-RyR CICR.


RESULTS
We differentially manipulated single RyR Ca(2+) flux amplitude and SR Ca(2+) load in permeabilized ventricular myocytes as an endogenous cell biology model of the heart. Large RyR-permeable organic cations were used to interfere with Ca(2+) conductance through the open RyR pore. Single-channel studies show this attenuates current amplitude without altering other aspects of RyR function. In cells, the same experimental maneuver increased resting SR Ca(2+) load. Despite the increased load, Ca(2+) spark (inter-RyR CICR events) frequency decreased and sparks terminated earlier.


CONCLUSIONS
Spark local control follows single RyR current amplitude, not simply SR Ca(2+) load. Spark frequency increases with load because spontaneous RyR openings at high loads produce larger currents (ie, a larger CICR trigger signal). Sparks terminate when load falls to the point at which single RyR current amplitude is no longer sufficient to sustain inter-RyR CICR. Thus, RyRs that spontaneously close no longer reopen and local Ca(2+) release ends.
Department of Molecular Biophysics and Physiology, Section of Cellular Signaling, Rush University Medical Center, Chicago, IL 60112, USA.
Tao
T
Guo
Dirk
D
Gillespie
Michael
M
Fill
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D004983:Ethanolamines / Q000378:metabolism; D025461:Feedback, Physiological; D005470:Fluorometry; D015640:Ion Channel Gating / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials; D008861:Microsomes; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D004983:Ethanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; C009546:triethanolamine; D008274:Magnesium; D008239:Lysine; D011188:Potassium