title: Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes.
abstract: BACKGROUND
  Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca(2+) release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated after Gαq-protein-coupled receptor stimulation, affecting Ca(2+) cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias.
  
  
  RESULTS
  IP3R function was determined in human left ventricular myocytes, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human left ventricular myocytes. After Gαq-protein-coupled receptor activation, Ca(2+) mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca(2+) transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca(2+) elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that Gαq-protein-coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca(2+) load by IP3Rs promote Ca(2+) extrusion by forward-mode Na(+)/Ca(2+) exchange, an important mechanism of arrhythmic events.
  
  
  CONCLUSIONS
  The Gαq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.
authors: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.S., A.S., J.F.-M., R.K., M.S., F.D.B., K.I., C.A., E.W., A.W., F.S., B.O., H.Z., X.L., T.H., P.G., A.L., J.K., P.A., M.R.); Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.d.M.); and Department of Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY (D.A.D., O.W., R.E.M.).
authors: Sergio
authors: S
authors: Signore
authors: Andrea
authors: A
authors: Sorrentino
authors: João
authors: J
authors: Ferreira-Martins
authors: Ramaswamy
authors: R
authors: Kannappan
authors: Mehrdad
authors: M
authors: Shafaie
authors: Fabio
authors: F
authors: Del Ben
authors: Kazuya
authors: K
authors: Isobe
authors: Christian
authors: C
authors: Arranto
authors: Ewa
authors: E
authors: Wybieralska
authors: Andrew
authors: A
authors: Webster
authors: Fumihiro
authors: F
authors: Sanada
authors: Barbara
authors: B
authors: Ogórek
authors: Hanqiao
authors: H
authors: Zheng
authors: Xiaoxia
authors: X
authors: Liu
authors: Federica
authors: F
authors: Del Monte
authors: David A
authors: DA
authors: D'Alessandro
authors: Oriyanhan
authors: O
authors: Wunimenghe
authors: Robert E
authors: RE
authors: Michler
authors: Toru
authors: T
authors: Hosoda
authors: Polina
authors: P
authors: Goichberg
authors: Annarosa
authors: A
authors: Leri
authors: Jan
authors: J
authors: Kajstura
authors: Piero
authors: P
authors: Anversa
authors: Marcello
authors: M
authors: Rota
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C506926:ITPR1 protein, human; C506927:ITPR2 protein, human; C506929:ITPR3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: arrhythmias, cardiac; calcium; inositol 1,4,5-trisphosphate receptors; myocytes, cardiac
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