PMID- 24042497
OWN - NLM
STAT- MEDLINE
DCOM- 20150413
LR  - 20220316
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 591
IP  - 21
DP  - 2013 Nov 1
TI  - The emergence of subcellular pacemaker sites for calcium waves and oscillations.
PG  - 5305-20
LID - 10.1113/jphysiol.2013.259960 [doi]
AB  - Calcium (Ca(2+)) waves generating oscillatory Ca(2+) signals are widely observed 
      in biological cells. Experimental studies have shown that under certain 
      conditions, initiation of Ca(2+) waves is random in space and time, while under 
      other conditions, waves occur repetitively from preferred locations (pacemaker 
      sites) from which they entrain the whole cell. In this study, we use computer 
      simulations to investigate the self-organization of Ca(2+) sparks into pacemaker 
      sites generating Ca(2+) oscillations. In both ventricular myocyte experiments and 
      computer simulations of a heterogeneous Ca(2+) release unit (CRU) network model, 
      we show that Ca(2+) waves occur randomly in space and time when the Ca(2+) level 
      is low, but as the Ca(2+) level increases, waves occur repetitively from the same 
      sites. Our analysis indicates that this transition to entrainment can be 
      attributed to the fact that random Ca(2+) sparks self-organize into Ca(2+) 
      oscillations differently at low and high Ca(2+) levels. At low Ca(2+), the whole 
      cell Ca(2+) oscillation frequency of the coupled CRU system is much slower than 
      that of an isolated single CRU. Compared to a single CRU, the distribution of 
      interspike intervals (ISIs) of the coupled CRU network exhibits a greater 
      variation, and its ISI distribution is asymmetric with respect to the peak, 
      exhibiting a fat tail. At high Ca(2+), however, the coupled CRU network has a 
      faster frequency and lesser ISI variation compared to an individual CRU. The ISI 
      distribution of the coupled network no longer exhibits a fat tail and is 
      well-approximated by a Gaussian distribution. This same Ca(2+) oscillation 
      behaviour can also be achieved by varying the number of ryanodine receptors per 
      CRU or the distance between CRUs. Using these results, we develop a theory for 
      the entrainment of random oscillators which provides a unified explanation for 
      the experimental observations underlying the emergence of pacemaker sites and 
      Ca(2+) oscillations.
FAU - Nivala, Michael
AU  - Nivala M
AD  - Z. Qu: Department of Medicine, David Geffen School of Medicine at UCLA, A2-237 
      CHS, 650 Charles E. Young Drive South, Los Angeles, CA 90095. 
      zqu@mednet.ucla.edu.
FAU - Ko, Christopher Y
AU  - Ko CY
FAU - Nivala, Melissa
AU  - Nivala M
FAU - Weiss, James N
AU  - Weiss JN
FAU - Qu, Zhilin
AU  - Qu Z
LA  - eng
GR  - P01 HL078931/HL/NHLBI NIH HHS/United States
GR  - T32 GM065823/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130916
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
SB  - IM
MH  - *Action Potentials
MH  - Animals
MH  - *Calcium Signaling
MH  - Computer Simulation
MH  - Heart Ventricles/cytology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Myocytes, Cardiac/*metabolism/physiology
PMC - PMC3936369
EDAT- 2013/09/18 06:00
MHDA- 2015/04/14 06:00
PMCR- 2014/11/01
CRDT- 2013/09/18 06:00
PHST- 2013/09/18 06:00 [entrez]
PHST- 2013/09/18 06:00 [pubmed]
PHST- 2015/04/14 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - jphysiol.2013.259960 [pii]
AID - 10.1113/jphysiol.2013.259960 [doi]
PST - ppublish
SO  - J Physiol. 2013 Nov 1;591(21):5305-20. doi: 10.1113/jphysiol.2013.259960. Epub 
      2013 Sep 16.