scholarly journals Inositol 1,4,5-trisphosphate receptor expression in cardiac myocytes.

1993 ◽  
Vol 120 (5) ◽  
pp. 1137-1146 ◽  
Author(s):  
M C Moschella ◽  
A R Marks
Keyword(s):  
Intracellular Calcium ◽  
Cardiac Myocytes ◽  
Calcium Release ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Rnase Protection ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Calcium Release

Calcium release from intracellular stores is the signal generated by numerous regulatory pathways including those mediated by hormones, neurotransmitters and electrical activation of muscle. Recently two forms of intracellular calcium release channels (CRCs) have been identified. One, the inositol 1,4,5-trisphosphate receptors (IP3Rs) mediate IP3-induced Ca2+ release and are believed to be present on the ER of most cell types. A second form, the ryanodine receptors (RYRs) of the sarcoplasmic reticulum, have evolved specialized functions relevant to muscle contraction and are the major CRCs found in striated muscles. Though structurally related, IP3Rs and RYRs have distinct physiologic and pharmacologic profiles. In the heart, where the dominant mechanism of intracellular calcium release during excitation-contraction coupling is Ca(2+)-induced Ca2+ release via the RYR, a role for IP3-mediated Ca2+ release has also been proposed. It has been assumed that IP3Rs are expressed in the heart as in most other tissues, however, it has not been possible to state whether cardiac IP3Rs were present in cardiac myocytes (which already express abundant amounts of RYR) or only in non-muscle cells within the heart. This lack of information regarding the expression and structure of an IP3R within cardiac myocytes has hampered the elucidation of the significance of IP3 signaling in the heart. In the present study we have used combined in situ hybridization to IP3R mRNA and immunocytochemistry to demonstrate that, in addition to the RYR, an IP3R is also expressed in rat cardiac myocytes. Immunoreactivity and RNAse protection have shown that the IP3R expressed in cardiac myocytes is structurally similar to the IP3R in brain and vascular smooth muscle. Within cardiac myocytes, IP3R mRNA levels were approximately 50-fold lower than that of the cardiac RYR mRNA. Identification of an IP3R in cardiac myocytes provides the basis for future studies designed to elucidate its functional role both as a mediator of pharmacologic and hormonal influences on the heart, and in terms of its possible interaction with the RYR during excitation-contraction coupling in the heart.

The Chemical Transmission Mechanism of Excitation-Contraction Coupling in Skeletal Muscle

Physiology ◽  
1987 ◽  
Vol 2 (5) ◽  
pp. 182-186 ◽  
Author(s):  
J Vergara ◽  
K Asotra
Keyword(s):  
Skeletal Muscle ◽  
Action Potential ◽  
Calcium Release ◽  
Transmission Mechanism ◽  
Temperature Dependent ◽  
Transverse Tubules ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Vertebrate Muscle ◽  
Inositol 1,4,5 Trisphosphate

There is a temperature-dependent lag between depolarization of transverse tubules by the action potential and onset of calcium release from the sacromplasmic reticulum that reveals the occurrence of a chemical step in excitation-contraction coupling. Recent studies suggest that in vertebrate muscle inositol 1,4,5-trisphosphate may act as a chemical link in this process.

scholarly journals T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.

1997 ◽  
Vol 17 (6) ◽  
pp. 3005-3012 ◽  
Author(s):  
T Jayaraman ◽  
A R Marks
Keyword(s):  
T Cells ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Calcium Influx ◽  
Cell Receptor ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Calcium Release ◽  
Trisphosphate Receptor

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.

Calcium release from cardiac sarcoplasmic reticulum induced by photorelease of calcium or Ins(1,4,5)P3

1990 ◽  
Vol 258 (2) ◽  
pp. H610-H615 ◽  
Author(s):  
J. C. Kentish ◽  
R. J. Barsotti ◽  
T. J. Lea ◽  
I. P. Mulligan ◽  
J. R. Patel ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Muscle ◽  
Calcium Release ◽  
Force Response ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Excitation Contraction Coupling ◽  
Caged Compounds ◽  
Contraction Coupling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Ventricular Trabeculae

The ability of Ca2+ or inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] to release Ca2+ from cardiac sarcoplasmic reticulum (SR) was investigated using saponin-skinned ventricular trabeculae from rats. To overcome diffusion delays, rapid increases in the concentrations of Ca2+ and Ins(1,4,5)P3 were produced by laser photolysis of “caged Ca2+” (Nitr-5) and “caged Ins(1,4,5)P3”. Photolysis of Nitr-5 to produce a small jump in [Ca2+] from pCa 6.8 to 6.4 induced a large and rapid force response (t1/2 = 0.89 s at 12 degrees C); the source of the Ca2+ that activated the myofibrils was judged to be the SR, since it was blocked by 0.1 mM ryanodine or 5 mM caffeine. A smaller, slower, and less consistent release of SR Ca2+ was produced by photorelease of Ins(1,4,5)P3. The results demonstrate that these caged compounds can be used to study excitation-contraction coupling in skinned multicellular preparations of cardiac muscle. The data are consistent with a major role for Ca2(+)-induced Ca2+ release in cardiac activation, whereas the role for Ins(1,4,5)P3 may be to modulate, rather than directly stimulate, SR Ca2+ release.

scholarly journals Ca2+ release via IP3Rs increases RyR mediated Ca2+ spark frequency in ventricular cardiomyocytes without altering spark amplitude and duration

2020 ◽  
Author(s):  
Agnė Tilūnaitė ◽  
David Ladd ◽  
Hilary Hunt ◽  
Christian Soeller ◽  
H. Llewelyn Roderick ◽  
...  
Keyword(s):  
Calcium Release ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Cardiac Cells ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Regulate Cell Growth ◽  
Biochemical Signals ◽  
The Impact

AbstractCalcium plays critical roles in cardiac cells, coupling electrical excitation to mechanical contraction with each heartbeat, while simultaneously mediating biochemical signals that regulate cell growth. While ryanodine receptors (RyRs) are fundamental to generation of elementary calcium release events (sparks) and global calcium elevations that underlie excitation-contraction coupling (ECC), calcium release via inositol 1,4,5-trisphosphate receptors (IP3Rs) is also reported in cardiomyocytes. IP3R calcium release modifies ECC as well as contributing to downstream regulation of hypertrophic gene expression. Recent studies suggest that proximal localisation of IP3Rs with RyRs contributes to their ability to modify Ca2+ handling during ECC. Here we aim to determine the mechanism by which IP3Rs modify Ca2+ handling in cardiomyocytes. We develop a mathematical model incorporating the stochastic behaviour of receptor opening that allows for the parametric tuning of the system to reveal the impact of IP3Rs on spark activation. By testing multiple spark initiation mechanisms, we find that Ca2+ release via IP3Rs result in increased propensity for spark initiation within the cardiac dyad. Our simulations suggest that opening of IP3Rs elevates Ca2+ within the dyad, which increase the probability of spark initiation. Finally, we find that while increasing the number of IP3Rs increases the probability of spark formation, it has little effect on spark amplitude, duration, or overall shape. Our study therefore suggests that IP3R play a critical role in modulating Ca2+ signaling for excitation contraction couplingAuthor summaryWhile Ca2+ release through ryanodine receptors (RyRs) initiates contraction in cardiomyocytes, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in cardiomyocytes is less clear with Ca2+ release through these channels being invoked in regulating ECC and hypertrophic signalling. RyRs generate cytosolic Ca2+ signals through elemental Ca2+ release events called sparks. The mechanisms by which IP3Rs influence cytosolic Ca2+ are not well understood. We created a 1D model of calcium spark formation in a cardiomyocyte dyad—the primary site of elemental RyR-based calcium release. We investigated possible behaviours of IP3Rs and their interaction with RyRs in generating Ca2+ sparks. We show that for high IP3 concentration, a large number of IP3Rs and high IP3R affinity are required to noticeably affect spark shape. At lower IP3 concentration IP3Rs can increase Ca2+ spark activity, but do not significantly alter the spark shape. Finally our simulations suggest that spark frequency can be reliably increased when IP3Rs activity is such that a small continuous Ca2+ flux is introduced to the dyad to elevate Ca2+, and not via brief but high Ca2+ release from these receptors.

scholarly journals Studying dyadic structure–function relationships: a review of current modeling approaches and new insights into Ca2+ (mis)handling

2017 ◽  
Vol 11 ◽  
pp. 117954681769860 ◽  
Author(s):  
Mary M Maleckar ◽  
Andrew G Edwards ◽  
William E Louch ◽  
Glenn T Lines
Keyword(s):  
Heart Disease ◽  
Sarcoplasmic Reticulum ◽  
Structure Function ◽  
Cardiac Myocytes ◽  
Calcium Release ◽  
Calcium Handling ◽  
Protein Distribution ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Calcium Dependent

Excitation–contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation–contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells’ calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation–contraction coupling have been increasingly employed to probe these structure–function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.

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