Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes

Sergio Signore, Andrea Sorrentino, João Ferreira-Martins, Ramaswamy Kannappan, Mehrdad Shafaie, Fabio Del Ben, Kazuya Isobe, Christian Arranto, Ewa Wybieralska, Andrew Webster, Fumihiro Sanada, Barbara Ogórek, Hanqiao Zheng, Xiaoxia Liu, Federica Del Monte, David A. D'Alessandro, Oriyanhan Wunimenghe, Robert E. Michler, Toru Hosoda, Polina Goichberg & 4 others Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1286-1297
Number of pages12
JournalCirculation
Volume128
Issue number12
DOIs
StatePublished - Sep 17 2013

Fingerprint

Gq-G11 GTP-Binding Protein alpha Subunits
Inositol 1,4,5-Trisphosphate Receptors
Muscle Cells
Myocardium
Cardiac Myocytes
Cardiac Arrhythmias
Sarcoplasmic Reticulum
Membrane Potentials
Action Potentials
Incidence

Keywords

  • arrhythmias
  • calcium
  • cardiac
  • inositol 1,4,5-trisphosphate receptors
  • myocytes, cardiac

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Signore, S., Sorrentino, A., Ferreira-Martins, J., Kannappan, R., Shafaie, M., Del Ben, F., ... Rota, M. (2013). Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation, 128(12), 1286-1297. https://doi.org/10.1161/CIRCULATIONAHA.113.002764

Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. / Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João; Kannappan, Ramaswamy; Shafaie, Mehrdad; Del Ben, Fabio; Isobe, Kazuya; Arranto, Christian; Wybieralska, Ewa; Webster, Andrew; Sanada, Fumihiro; Ogórek, Barbara; Zheng, Hanqiao; Liu, Xiaoxia; Del Monte, Federica; D'Alessandro, David A.; Wunimenghe, Oriyanhan; Michler, Robert E.; Hosoda, Toru; Goichberg, Polina; Leri, Annarosa; Kajstura, Jan; Anversa, Piero; Rota, Marcello.

In: Circulation, Vol. 128, No. 12, 17.09.2013, p. 1286-1297.

Research output: Contribution to journalArticle

Signore, S, Sorrentino, A, Ferreira-Martins, J, Kannappan, R, Shafaie, M, Del Ben, F, Isobe, K, Arranto, C, Wybieralska, E, Webster, A, Sanada, F, Ogórek, B, Zheng, H, Liu, X, Del Monte, F, D'Alessandro, DA, Wunimenghe, O, Michler, RE, Hosoda, T, Goichberg, P, Leri, A, Kajstura, J, Anversa, P & Rota, M 2013, 'Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes', Circulation, vol. 128, no. 12, pp. 1286-1297. https://doi.org/10.1161/CIRCULATIONAHA.113.002764
Signore S, Sorrentino A, Ferreira-Martins J, Kannappan R, Shafaie M, Del Ben F et al. Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation. 2013 Sep 17;128(12):1286-1297. https://doi.org/10.1161/CIRCULATIONAHA.113.002764
Signore, Sergio ; Sorrentino, Andrea ; Ferreira-Martins, João ; Kannappan, Ramaswamy ; Shafaie, Mehrdad ; Del Ben, Fabio ; Isobe, Kazuya ; Arranto, Christian ; Wybieralska, Ewa ; Webster, Andrew ; Sanada, Fumihiro ; Ogórek, Barbara ; Zheng, Hanqiao ; Liu, Xiaoxia ; Del Monte, Federica ; D'Alessandro, David A. ; Wunimenghe, Oriyanhan ; Michler, Robert E. ; Hosoda, Toru ; Goichberg, Polina ; Leri, Annarosa ; Kajstura, Jan ; Anversa, Piero ; Rota, Marcello. / Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. In: Circulation. 2013 ; Vol. 128, No. 12. pp. 1286-1297.
@article{764e4293e0b44a4a9d1ac01ffd27ec66,
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 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.",
keywords = "arrhythmias, calcium, cardiac, inositol 1,4,5-trisphosphate receptors, myocytes, cardiac",
author = "Sergio Signore and Andrea Sorrentino and Jo{\~a}o Ferreira-Martins and Ramaswamy Kannappan and Mehrdad Shafaie and {Del Ben}, Fabio and Kazuya Isobe and Christian Arranto and Ewa Wybieralska and Andrew Webster and Fumihiro Sanada and Barbara Og{\'o}rek and Hanqiao Zheng and Xiaoxia Liu and {Del Monte}, Federica and D'Alessandro, {David A.} and Oriyanhan Wunimenghe and Michler, {Robert E.} and Toru Hosoda and Polina Goichberg and Annarosa Leri and Jan Kajstura and Piero Anversa and Marcello Rota",
year = "2013",
month = "9",
day = "17",
doi = "10.1161/CIRCULATIONAHA.113.002764",
language = "English (US)",
volume = "128",
pages = "1286--1297",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

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

UR - http://www.scopus.com/inward/record.url?scp=84884268504&partnerID=8YFLogxK

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

VL - 128

SP - 1286

EP - 1297

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 12

ER -