K201 (JTV519) is a Ca<sup>2+</sup>-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle

Darcy, Yuanzhao L.; Diaz-Sylvester, Paula L.; Copello, Julio A.

doi:10.1124/mol.115.102277

Cited by 10 publications

(11 citation statements)

References 56 publications

(88 reference statements)

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“…They were snap-frozen with liquid N 2 and stored at −80°C. For spectroscopic measurements, aliquots were quickly thawed in water, incubated on ice, and used within 3 h. Ca 2+ uptake by cardiac SR microsomes was measured as previously described ( Neumann and Copello, 2011 ; Darcy et al, 2016 ). Ca 2+ uptake was initiated by adding 40 nM CaCl 2 to a cuvette containing 100 µg SR membranes suspended in 1 ml buffer (in mM: 100 KH 2 PO 4 , 5 MgCl 2 (∼0.3 mM free Mg 2+ ), 5 ATP, and 0.2 absorbance Ca 2+ indicator antipyrylazo III, pH 7.0).…”

Section: Methodsmentioning

confidence: 99%

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Millet

Aguilar-Sánchez

Kornyeyev

et al. 2021

Journal of General Physiology

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Ca2+ alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca2+ transients that frequently occur during tachycardia, ischemia, or hypothermia that can lead to sudden cardiac death. Ca-Alts appear to result from a variation in the amount of Ca2+ released from the sarcoplasmic reticulum (SR) between two consecutive heartbeats. This variable Ca2+ release has been attributed to the alternation of the action potential duration, delay in the recovery from inactivation of RYR Ca2+ release channel (RYR2), or an incomplete Ca2+ refilling of the SR. In all three cases, the RYR2 mobilizes less Ca2+ from the SR in an alternating manner, thereby generating an alternating profile of the Ca2+ transients. We used a new experimental approach, fluorescence local field optical mapping (FLOM), to record at the epicardial layer of an intact heart with subcellular resolution. In conjunction with a local cold finger, a series of images were recorded within an area where the local cooling induced a temperature gradient. Ca-Alts were larger in colder regions and occurred without changes in action potential duration. Analysis of the change in the enthalpy and Q10 of several kinetic processes defining intracellular Ca2+ dynamics indicated that the effects of temperature change on the relaxation of intracellular Ca2+ transients involved both passive and active mechanisms. The steep temperature dependency of Ca-Alts during tachycardia suggests Ca-Alts are generated by insufficient SERCA-mediated Ca2+ uptake into the SR. We found that Ca-Alts are heavily dependent on intra-SR Ca2+ and can be promoted through partial pharmacologic inhibition of SERCA2a. Finally, the FLOM experimental approach has the potential to help us understand how arrhythmogenesis correlates with the spatial distribution of metabolically impaired myocytes along the myocardium.

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Section: Methodsmentioning

confidence: 99%

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Millet

Aguilar-Sánchez

Kornyeyev

et al. 2021

Journal of General Physiology

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“…To determine whether SR-Ca 2+ cycling is a prerequisite for SLN signaling, we manipulated SR-Ca 2+ release in myotubes using caffeine to sensitize ( Darcy et al, 2016 ) and dantrolene to inhibit RYR1, the primary Ca 2+ release channel in skeletal muscle SR ( Cherednichenko et al, 2008 ). Treatment with 3.5 mM caffeine resulted in an increase in phosphorylated Ca2+/calmodulin-dependent protein kinase II (pCamKII) activation and Mef2c expression in WT myotubes, but not in Sln -KO myotubes ( Figure 4D ).…”

Section: Resultsmentioning

confidence: 99%

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

et al. 2018

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The major objective of this study was to understand the molecular basis of how sarcolipin uncoupling of SERCA regulates muscle oxidative metabolism. Using genetically engineered sarcolipin (SLN) mouse models and primary muscle cells, we demonstrate that SLN plays a crucial role in mitochondrial biogenesis and oxidative metabolism in muscle. Loss of SLN severely compromised muscle oxidative capacity without affecting fiber-type composition. Mice overexpressing SLN in fast-twitch glycolytic muscle reprogrammed mitochondrial phenotype, increasing fat utilization and protecting against high-fat diet-induced lipotoxicity. We show that SLN affects cytosolic Ca transients and activates the Ca/calmodulin-dependent protein kinase II (CamKII) and PGC1α axis to increase mitochondrial biogenesis and oxidative metabolism. These studies provide a fundamental framework for understanding the role of sarcoplasmic reticulum (SR)-Ca cycling as an important factor in mitochondrial health and muscle metabolism. We propose that SLN can be targeted to enhance energy expenditure in muscle and prevent metabolic disease.

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“…The Rycal class of drugs emerged from initial work using K201 (JTV-519), a compound first described in the early 1990s [128] that has shown mixed effects on RyR1-mediated Ca2 + release in vitro and may diminish SR Ca 2+ re-uptake via SERCA [129]. Owing to this nonspecific mechanism of action, a number of refined JTV-519-derivatives have since been developed including the first Rycal compound to be tested clinically (ARM036; Aladorian), and the current lead Rycal compound (ARM210; S48168).…”

Section: Ryr1-rm Therapeutic Approachesmentioning

confidence: 99%

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

2018

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Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core–rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.

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K201 (JTV519) is a Ca²⁺-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle

Abstract: K201 (JTV-519) may prevent abnormal Ca 21 leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca

Cited by 10 publications

References 56 publications

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

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K201 (JTV519) is a Ca2+-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle

Abstract: K201 (JTV-519) may prevent abnormal Ca 21 leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca

Cited by 10 publications

References 56 publications

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

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K201 (JTV519) is a Ca²⁺-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle