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.

Avian Extended Junctional SR: 3-D Geometry Rendered in Stereo

1997 ◽  
Vol 3 (S2) ◽  
pp. 247-248
Author(s):  
J.R. Sommer ◽  
T. High ◽  
P. Ingram ◽  
D. Kopf ◽  
R. Nassar ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Muscle Contraction ◽  
Cardiac Myocytes ◽  
Ryanodine Receptor ◽  
Transverse Tubules ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Junctional Sarcoplasmic Reticulum ◽  
Invariant Differentiation

Extended junctional sarcoplasmic reticulum (EJSR) is an invariant differentiation of the sarcoplasmic reticulum (SR) in bird cardiac myocytes (CM) and central to excitation-contraction coupling (ECC). EJSR occurs as both continuous and discontinuous extensions of junctional sarcoplasmic reticulum (JSR), and surrounds and pervades the Z/I band as the “ EJSR Z-rete” whose geometry has mechanistic implications for the function of “couplings” in ECC, in general. “Peripheral coupling(s)” (PC) in birds, and the additional “interior coupling(s)” (IC) at transverse tubules (TT) in mammals, are formed by tight apposition to plasmalemma of JSR, a specialized calcium (Ca) store of the SR. Free SR (FSR; i.e. free of JSR/EJSR specializations) is the rest of the smooth, tubular SR network, which connects intercalated patches of EJSR forming the EJSR Z-retes and, elsewhere, displays both longitudinal and transverse geometries in surrounding the contractile material for the purpose of sequestering Ca after each muscle contraction. Except for EJSR having no plasmalemmal contact, morphologically, EJSR and JSR are homologues:1 both have similar sizes; are studded (approx. 32 nm center-to-center) with junctional processes (JP; ryanodine receptor (RyR)/-Ca-release channels);

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 Excitation Contraction Coupling in Hypertrophy and Failing Heart Cells

2021 ◽  
Vol 271 ◽  
pp. 03008
Author(s):  
Yiqiu Zhou
Keyword(s):  
Heart Failure ◽  
Calcium Release ◽  
Heart Diseases ◽  
Calcium Handling ◽  
Heart Cells ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Failing Heart ◽  
Failure Models ◽  
And Function

The contraction of the heart is dependent on a process named the excitation-contraction coupling (E-C coupling). In hypertrophy and failing heart models, the expression, phosphorylation and function of key calcium handling proteins involved in E-C coupling are altered. It’s important to figure out the relationship changes between calcium channel activity and calcium release from sarcoplasmic reticulum (SR). This review will therefore focus on novel components of E-C coupling dysfunction in hypertrophy and failing heart, such as L-type Ca2+ channel (LCC), ryanodine receptor type-2 channel (RyR2) and SR Ca ATPase (SERCA), and how these molecular modifications altered excitation-contraction coupling. A lot of literature was well read and sorted. Recent findings in E-C coupling during hypertrophy and heart failure were focused on. Most importantly, the electrophysiological and signal pathway data was carefully analyzed. This review summarizes key principles and highlights novel aspects of E-C coupling changes during hypertrophy and heart failure models. Although LCC activity changed little, the loss of notch in action potential, reduced Ca2+ transient amplitude and desynchronized Ca2+ sparks resulted in a decreased contraction strength in hypertrophy and heart failure models. What’s more, L-type Ca2+ current becomes ineffective in triggering RyR2 Ca2+ release from SR and the SR uptake is reduced in some models. It has great meanings in understanding the E-C coupling changes during different heart diseases. Theses novel changes suggest potential therapeutic approaches for certain types of hypertrophy and heart failure.

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.

scholarly journals Spontaneous calcium release in tissue from the failing canine heart

2009 ◽  
Vol 297 (4) ◽  
pp. H1235-H1242 ◽  
Author(s):  
Gregory S. Hoeker ◽  
Rodolphe P. Katra ◽  
Lance D. Wilson ◽  
Bradley N. Plummer ◽  
Kenneth R. Laurita
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Tissue Level ◽  
Calcium Handling ◽  
Canine Heart ◽  
Myocardial Cells ◽  
Spontaneous Release ◽  
Adrenergic Stimulation ◽  
Electrical Instability ◽  
Delayed Afterdepolarization

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during β-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.

scholarly journals Triadin Binding to the C-Terminal Luminal Loop of the Ryanodine Receptor is Important for Skeletal Muscle Excitation–Contraction Coupling

2007 ◽  
Vol 130 (4) ◽  
pp. 365-378 ◽  
Author(s):  
Sanjeewa A. Goonasekera ◽  
Nicole A. Beard ◽  
Linda Groom ◽  
Takashi Kimura ◽  
Alla D. Lyfenko ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Striated Muscle ◽  
Single Channel ◽  
Triple Mutant ◽  
Double Mutation ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Functional Studies

Ca2+ release from intracellular stores is controlled by complex interactions between multiple proteins. Triadin is a transmembrane glycoprotein of the junctional sarcoplasmic reticulum of striated muscle that interacts with both calsequestrin and the type 1 ryanodine receptor (RyR1) to communicate changes in luminal Ca2+ to the release machinery. However, the potential impact of the triadin association with RyR1 in skeletal muscle excitation–contraction coupling remains elusive. Here we show that triadin binding to RyR1 is critically important for rapid Ca2+ release during excitation–contraction coupling. To assess the functional impact of the triadin-RyR1 interaction, we expressed RyR1 mutants in which one or more of three negatively charged residues (D4878, D4907, and E4908) in the terminal RyR1 intraluminal loop were mutated to alanines in RyR1-null (dyspedic) myotubes. Coimmunoprecipitation revealed that triadin, but not junctin, binding to RyR1 was abolished in the triple (D4878A/D4907A/E4908A) mutant and one of the double (D4907A/E4908A) mutants, partially reduced in the D4878A/D4907A double mutant, but not affected by either individual (D4878A, D4907A, E4908A) mutations or the D4878A/E4908A double mutation. Functional studies revealed that the rate of voltage- and ligand-gated SR Ca2+ release were reduced in proportion to the degree of interruption in triadin binding. Ryanodine binding, single channel recording, and calcium release experiments conducted on WT and triple mutant channels in the absence of triadin demonstrated that the luminal loop mutations do not directly alter RyR1 function. These findings demonstrate that junctin and triadin bind to different sites on RyR1 and that triadin plays an important role in ensuring rapid Ca2+ release during excitation–contraction coupling in skeletal muscle.

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