title: Mathematical model of mouse embryonic cardiomyocyte excitation-contraction coupling.
abstract: Excitation-contraction (E-C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca(2+) signals and contractions (E-C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca(2+) releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na(+)/Ca(2+) exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca(2+) intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E-C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca(2+) dynamics and oscillatory SR Ca(2+) handling. The model reproduces faithfully the experimentally observed fundamental features of both E-C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.
authors.affiliation: Institute of Biomedicine, Department of Physiology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
authors.forename: Topi
authors.initials: T
authors.lastname: Korhonen
authors.forename: Risto
authors.initials: R
authors.lastname: Rapila
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D004622:Embryo, Mammalian / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology; D051379:Mice; D008955:Models, Cardiovascular; D050505:Mutant Proteins; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D037282:Calreticulin; D050505:Mutant Proteins; D019831:Sodium-Calcium Exchanger; D002118:Calcium
references.citation: J Physiol. 1983 Apr;337:401-16
references.pmid: 6875938
references.citation: Biophys J. 1998 Mar;74(3):1149-68
references.pmid: 9512016
references.citation: J Clin Invest. 2001 May;107(10):1245-53
references.pmid: 11375414
references.citation: Ann N Y Acad Sci. 2005 Jun;1047:138-56
references.pmid: 16093492
references.citation: J Biol Chem. 1997 Sep 19;272(38):23961-9
references.pmid: 9295347
references.citation: J Biol Chem. 2000 Dec 15;275(50):39193-9
references.pmid: 10973973
references.citation: Circ Res. 2001 Jun 22;88(12):1254-8
references.pmid: 11420301
references.citation: Mol Biol Cell. 2005 May;16(5):2414-23
references.pmid: 15758029
references.citation: Biophys J. 2004 Feb;86(2):966-77
references.pmid: 14747332
references.citation: Physiol Rev. 1991 Jan;71(1):53-91
references.pmid: 1986392
references.citation: Biophys J. 1993 Oct;65(4):1727-39
references.pmid: 8274661
references.citation: J Mol Cell Cardiol. 2000 May;32(5):839-51
references.pmid: 10775488
references.citation: Biophys J. 1998 Aug;75(2):834-9
references.pmid: 9675184
references.citation: Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9895-9
references.pmid: 1329108
references.citation: Biophys J. 2000 Jul;79(1):271-8
references.pmid: 10866953
references.citation: Am J Physiol. 1996 May;270(5 Pt 2):H1772-8
references.pmid: 8928885
references.citation: Circ Res. 1992 Nov;71(5):1242-53
references.pmid: 1327578
references.citation: Nat Rev Genet. 2005 Nov;6(11):826-35
references.pmid: 16304598
references.citation: Arch Biochem Biophys. 1990 Apr;278(1):205-10
references.pmid: 2321958
references.citation: Biochemistry. 2000 Nov 21;39(46):14176-82
references.pmid: 11087366
references.citation: Biophys J. 2004 Nov;87(5):3351-71
references.pmid: 15347581
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2257-63
references.pmid: 14988077
references.citation: Circ Res. 2006 Sep 29;99(7):749-57
references.pmid: 16946137
references.citation: Nature. 1998 Nov 5;396(6706):81-4
references.pmid: 9817204
references.citation: Circ Res. 1994 Jun;74(6):1071-96
references.pmid: 7514509
references.citation: FASEB J. 2001 May;15(7):1209-11
references.pmid: 11344090
references.citation: J Gen Physiol. 2007 Aug;130(2):133-44
references.pmid: 17664344
references.citation: J Cell Biol. 1999 Mar 8;144(5):857-68
references.pmid: 10085286
references.citation: J Theor Biol. 1996 Aug 7;181(3):245-72
references.pmid: 8869126
references.citation: J Biol Chem. 2000 Nov 24;275(47):36991-8
references.pmid: 10967099
references.citation: Biophys J. 2001 Dec;81(6):3029-51
references.pmid: 11720973
references.citation: Circ Res. 2003 May 2;92(8):904-11
references.pmid: 12676813
references.citation: Biophys J. 2006 May 1;90(9):3120-33
references.pmid: 16500959
references.citation: Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1378-403
references.pmid: 15142845
references.citation: Biophys J. 2003 Sep;85(3):1392-405
references.pmid: 12944257
references.citation: EMBO J. 1998 Jun 15;17(12):3309-16
references.pmid: 9628868
references.citation: Circ Res. 2001 Mar 16;88(5):536-42
references.pmid: 11249878
references.citation: Circ Res. 2001 Mar 2;88(4):403-7
references.pmid: 11230107
references.citation: J Gen Physiol. 2008 Oct;132(4):397-405
references.pmid: 18794377
references.citation: Circ Res. 1999 Sep 17;85(6):e7-e16
references.pmid: 10488061
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2398-403
references.pmid: 11842185
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15235-40
references.pmid: 14657344
references.citation: J Mol Cell Cardiol. 2007 Jan;42(1):121-32
references.pmid: 17157311
references.citation: Biophys J. 1996 Dec;71(6):3477-87
references.pmid: 8968617
references.citation: Biophys J. 2003 Nov;85(5):3388-96
references.pmid: 14581240