TY - JOUR
T1 - Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes
AU - Signore, Sergio
AU - Sorrentino, Andrea
AU - Ferreira-Martins, João
AU - Kannappan, Ramaswamy
AU - Shafaie, Mehrdad
AU - Del Ben, Fabio
AU - Isobe, Kazuya
AU - Arranto, Christian
AU - Wybieralska, Ewa
AU - Webster, Andrew
AU - Sanada, Fumihiro
AU - Ogórek, Barbara
AU - Zheng, Hanqiao
AU - Liu, Xiaoxia
AU - Del Monte, Federica
AU - D'Alessandro, David A.
AU - Wunimenghe, Oriyanhan
AU - Michler, Robert E.
AU - Hosoda, Toru
AU - Goichberg, Polina
AU - Leri, Annarosa
AU - Kajstura, Jan
AU - Anversa, Piero
AU - Rota, Marcello
PY - 2013/9/17
Y1 - 2013/9/17
N2 - BACKGROUND-: Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca 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 cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. METHODS AND 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 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 transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca 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 load by IP3Rs promote Ca extrusion by forward-mode Na/Ca 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.
AB - BACKGROUND-: Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca 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 cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. METHODS AND 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 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 transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca 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 load by IP3Rs promote Ca extrusion by forward-mode Na/Ca 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.
KW - arrhythmias
KW - calcium
KW - cardiac
KW - inositol 1,4,5-trisphosphate receptors
KW - myocytes, cardiac
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UR - http://www.scopus.com/inward/citedby.url?scp=84884268504&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.113.002764
DO - 10.1161/CIRCULATIONAHA.113.002764
M3 - Article
C2 - 23983250
AN - SCOPUS:84884268504
SN - 0009-7322
VL - 128
SP - 1286
EP - 1297
JO - Circulation
JF - Circulation
IS - 12
ER -