scholarly journals Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels

2022 ◽  
Vol 12 ◽  
Author(s):  
Rose E. Dixon

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers of their intracellular partners the type 2 ryanodine receptors (RyR2) which cluster on the junctional sarcoplasmic reticulum (jSR). The organization and distribution of these two groups of cardiac calcium channel clusters critically underlies the uniform contraction of the myocardium. Ca2+ signaling between these two sets of adjacent clusters produces Ca2+ sparks that in health, cannot escalate into Ca2+ waves because there is sufficient separation of adjacent clusters so that the release of Ca2+ from one RyR2 cluster or supercluster, cannot activate and sustain the release of Ca2+ from neighboring clusters. Instead, thousands of these Ca2+ release units (CRUs) generate near simultaneous Ca2+ sparks across every cardiomyocyte during the action potential when calcium induced calcium release from RyR2 is stimulated by depolarization induced Ca2+ influx through voltage dependent CaV1.2 channel clusters. These sparks summate to generate a global Ca2+ transient that activates the myofilaments and thus the electrical signal of the action potential is transduced into a functional output, myocardial contraction. To generate more, or less contractile force to match the hemodynamic and metabolic demands of the body, the heart responds to β-adrenergic signaling by altering activity of calcium channels to tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests that this tuning process also involves altered expression, and dynamic reorganization of CaV1.2 and RyR2 channels on their respective membranes to control the amplitude of Ca2+ entry, SR Ca2+ release and myocardial function. In heart failure and aging, altered distribution and reorganization of these key Ca2+ signaling proteins occurs alongside architectural remodeling and is thought to contribute to impaired contractile function. In the present review we discuss these latest developments, their implications, and future questions to be addressed.

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Yuichi Toyama ◽  
Manabu Yonekura ◽  
Chong Han ◽  
Hirofumi Tomita ◽  
Hiroshi Takeshima ◽  
...  

Trimeric intracellular cation (TRIC) channels are expressed on the surface of sarcoplasmic reticulum (SR) and regulate calcium release from ryanodine receptors (RyRs). In a previous study, Tric-a knock out (KO) mice showed diminished calcium release from RyRs following increased calcium-influx via L-type calcium channels, which results in enhanced vascular resistance and non-dipper type hypertension. Decreased activation of RyR1 by PKA in skeletal myocytes in Tric-a KO mice is also known. However, physiological importance of TRIC channels on cardiac rhythm formation and its importance on the sympathetic nerve regulation are still obscure. Therefore, we aimed to clarify the effects of Tric-a ablation on cardiac pace making using Tric-a KO mice. We measured systolic blood pressure (SBP) with tail-cuff method, ECG and spontaneous action potential with microelectrode in the Tric-a KO and wild type (WT) mice. Isoproterenol or propranolol was used for sympathetic nerve manipulation. Furthermore, we evaluated heart rate variability (HRV). Tric-a KO mice tended to show limited responses to isoproterenol (0.3 mg/kg) than the WT mice (-27 ± 6 and -32 ± 6 mmHg, n = 10, p =0.70), and to propranolol (4 ± 6 and 13 ± 7 mmHg, n = 5~6, p =0.48). In ECG analysis, ablation of Tric-a gene resulted in significantly decreased heart rate changes to isoproterenol (23 ± 6 and 99 ± 15 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). Response to propranolol was also significantly decreased in the Tric-a KO mice (-28 ± 20 and -122 ± 14 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). In the action potential recordings, Tric-a KO mice showed significantly decreased sinus rate changes to 1 microM isoproterenol (35 ± 9 and 71 ± 10 bpm, Tric-a KO and WT mice, respectively, n = 6~8, p <0.05). In HRV analysis, low-frequency/high-frequency (LF/HF) ratio tended to be lower in the Tric-a KO mice than the WT mice under the administration of isoproterenol (0.22 ± 0.31 and 0.65 ± 0.16 bpm, Tric-a KO and WT mice, respectively, n = 9~11, p =0.16), suggesting lower sympathetic nerve tonus in the Tric-a KO mice. In conclusion, our data indicates that Tric-a KO mice showed attenuated responses to beta-adrenergic stimulus, which indicates involvement of TRIC-A channels in sympathetic nerve regulation.


2008 ◽  
Vol 99 (3) ◽  
pp. 1565-1571 ◽  
Author(s):  
A. Tara Huddleston ◽  
Wei Tang ◽  
Hiroshi Takeshima ◽  
Susan L. Hamilton ◽  
Eric Klann

Reactive oxygen species (ROS) are required for the induction of long-term potentiation (LTP) and behave as signaling molecules via redox modifications of target proteins. In particular, superoxide is necessary for induction of LTP, and application of superoxide to hippocampal slices is sufficient to induce LTP in area CA1. Although a rise in postsynaptic intracellular calcium is necessary for LTP induction, superoxide-induced potentiation does not require calcium flux through N-methyl-d-aspartate (NMDA) receptors. Ryanodine receptors (RyRs) mediate calcium-induced calcium release from intracellular stores and have been shown to modulate LTP. In this study, we investigated the highly redox-sensitive RyRs and L-type calcium channels as calcium sources that might mediate superoxide-induced potentiation. In agreement with previous studies of skeletal and cardiac muscle, we found that superoxide enhances activation of RyRs in the mouse hippocampus. We identified a functional coupling between L-type voltage-gated calcium channels and RyRs and identified RyR3, a subtype enriched in area CA1, as the specific isoform required for superoxide-induced potentiation. Superoxide also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) in area CA1, and ERK was necessary for superoxide-induced potentiation. Thus superoxide-induced potentiation requires the redox targeting of RyR3 and the subsequent activation of ERK.


2012 ◽  
Vol 448 (2) ◽  
pp. 221-231 ◽  
Author(s):  
Tsutomu Nakada ◽  
Bernhard E. Flucher ◽  
Toshihide Kashihara ◽  
Xiaona Sheng ◽  
Toshihide Shibazaki ◽  
...  

In cardiac myocytes, LTCCs (L-type calcium channels) form a functional signalling complex with ryanodine receptors at the JM (junctional membrane). Although the specific localization of LTCCs to the JM is critical for excitation–contraction coupling, their targeting mechanism is unclear. Transient transfection of GFP (green fluorescent protein)–α1S or GFP–α1C, but not P/Q-type calcium channel α1A, in dysgenic (α1S-null) GLT myotubes results in correct targeting of these LTCCs to the JMs and restoration of action-potential-induced Ca2+ transients. To identify the sequences of α1C responsible for JM targeting, we generated a range of α1C–α1A chimaeras, deletion mutants and alanine substitution mutants and studied their targeting properties in GLT myotubes. The results revealed that amino acids L1681QAGLRTL1688 and P1693EIRRAIS1700, predicted to form two adjacent α-helices in the proximal C-terminus, are necessary for the JM targeting of α1C. The efficiency of restoration of action-potential-induced Ca2+ transients in GLT myotubes was significantly decreased by mutations in the targeting motif. JM targeting was not disrupted by the distal C-terminus of α1C which binds to the second α-helix. Therefore we have identified a new structural motif in the C-terminus of α1C that mediates the targeting of cardiac LTCCs to JMs independently of the interaction between proximal and distal C-termini of α1C.


2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Arianne Papa ◽  
Jared Kushner ◽  
Steven O. Marx

Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


2003 ◽  
Vol 285 (1) ◽  
pp. R125-R131 ◽  
Author(s):  
Tsuneo Takenaka ◽  
Yoichi Ohno ◽  
Koichi Hayashi ◽  
Takao Saruta ◽  
Hiromichi Suzuki

To investigate the role of ryanodine receptors in glomerular arterioles, experiments were performed using an isolated perfused hydronephrotic kidney model. In the first series of studies, BAYK-8644 (300 nM), a calcium agonist, constricted afferent (19.6 ± 0.6 to 17.6 ± 0.5 μm, n = 6, P < 0.01) but not efferent arterioles. Furthermore, BAYK-8644 elicited afferent arteriolar oscillatory movements. Subsequent administration of nifedipine (1 μM) inhibited both afferent arteriolar oscillation and constriction by BAYK-8644 (to 19.4 ± 0.5 μm). In the second group, although BAYK-8644 constricted afferent arterioles treated with 1 μM of thapsigargin (19.7 ± 0.6 to 16.8 ± 0.6 μm, n = 5, P < 0.05), it failed to induce rhythmic contraction. Removal of extracellular calcium with EGTA (2 mM) reversed BAYK-8644-induced afferent arteriolar constriction (to 20.0 ± 0.5 μm). In the third series of investigations, ryanodine (10 μM) but not 2-aminoethoxyphenyl borate (100 μM) abolished afferent arteriolar vasomotion by BAYK-8644. In the fourth series of experiments, in the presence of caffeine (1 mM), the stronger activation of voltage-dependent calcium channels by higher potassium media resulted in greater afferent arteriolar constriction and faster oscillation. Our results indicate that L-type calcium channels are rich in preglomerular but not postglomerular microvessels. Furthermore, the present findings suggest that either prolonged calcium influx through voltage-dependent calcium channels (BAYK-8644) or sensitized ryanodine receptors (caffeine) is required to trigger periodic calcium release through ryanodine receptors in afferent arterioles.


Membranes ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 794
Author(s):  
Minh Tuan Hoang-Trong ◽  
Aman Ullah ◽  
William Jonathan Lederer ◽  
Mohsin Saleet Jafri

Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, [Ca2+]myo and [Ca2+]SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and [Na+]i and thus provides insight into how changes in electrical activity, [Na+]i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in [Na+]i and [Ca2+]myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.


2011 ◽  
Vol 209 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Priyanka De ◽  
Sreerupa Ghose Roy ◽  
Dipak Kar ◽  
Arun Bandyopadhyay

Ventricular dysfunction is one of the important side effects of the anti-inflammatory agent, glucocorticoid (GC). The present study was undertaken to examine whether abnormal calcium signaling is responsible for cardiac dysfunction due to an excess of GC hormone. The synthetic GC drug, dexamethasone (DEX), significantly (P<0.001, n=20) increased heart weight to body weight ratio, left ventricular remodeling, and fibrosis. The microarray analysis showed altered expression of several genes encoding calcium cycling/ion channel proteins in DEX-treated rat heart. The altered expression of some of the genes was validated by real-time PCR and western blotting analyses. The expression of the L-type calcium channels and calsequestrin was increased, whereas sarcoendoplasmic reticulum calcium transport ATPase 2a (SERCA2a) and junctin mRNAs were significantly reduced in DEX-treated rat left ventricular tissues. In neonatal rat ventricular cardiomyocytes, DEX also increased the level of mRNAs of atrial- and brain natriuretic peptides, L-type calcium channels, and calsequestrin after 24 h of treatment, which were mostly restored by mifepristone. The caffeine-induced calcium release was prolonged by DEX compared to the sharp release in control cardiomyocytes. Taken together, these data show that impaired calcium kinetics may be responsible for cardiac malfunction by DEX. The results are important in understanding the pathophysiology of the heart in patients treated with excess GC.


Author(s):  
Tamilarasi G P ◽  
Sabarees G

Oxidation is an essential reaction in the human body, which determines the expression of proteins in the body. This results in the altered expression like rapid growth resulting in cancers and other disorders. Many synthetic drugs are available in the market that is effective in limiting the free radical generation and the reaction of radicals with cells. Unfortunately, all those synthetic drugs were found to cause side effects and adverse effects in the body. But given the accuracy of the predictability of the results and administration, this research focuses on testing the anti-oxidant efficiency in rat models testing the biochemical parameters. Investigations have also been done on the anti-oxidant activity of Tectona, but every research was concentrated to prove the anti-oxidant activity only. extract had been tested for anti-oxidant activity by estimating various tissue parameters and it showed better activity. As predicted, there is a significant difference in the and results which can be explained are due to the physiological conditions that exist inside the body.


Genetics ◽  
1994 ◽  
Vol 137 (2) ◽  
pp. 483-498
Author(s):  
J Ahnn ◽  
A Fire

Abstract We have used available chromosomal deficiencies to screen for genetic loci whose zygotic expression is required for formation of body-wall muscle cells during embryogenesis in Caenorhabditis elegans. To test for muscle cell differentiation we have assayed for both contractile function and the expression of muscle-specific structural proteins. Monoclonal antibodies directed against two myosin heavy chain isoforms, the products of the unc-54 and myo-3 genes, were used to detect body-wall muscle differentiation. We have screened 77 deficiencies, covering approximately 72% of the genome. Deficiency homozygotes in most cases stain with antibodies to the body-wall muscle myosins and in many cases muscle contractile function is observed. We have identified two regions showing distinct defects in myosin heavy chain gene expression. Embryos homozygous for deficiencies removing the left tip of chromosome V fail to accumulate the myo-3 and unc-54 products, but express antigens characteristic of hypodermal, pharyngeal and neural development. Embryos lacking a large region on chromosome III accumulate the unc-54 product but not the myo-3 product. We conclude that there exist only a small number of loci whose zygotic expression is uniquely required for adoption of a muscle cell fate.


2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Seong-Jong Kim ◽  
Hye Hyeon Han ◽  
Sei Kwang Hahn

Abstract Background Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. Methods We developed hyaluronate-diaminohexane/black phosphorus (HA-DAH/BP) complexes for capturing copper ions accumulated in the liver for the treatment of WD. Results HA-DAH/BP complexes showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-DAH/BP complexes to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-DAH/BP complexes. Conclusion HA-DAH/BP complexes would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.


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