A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201

Blayney, Lynda Mary; Jones, Jonathan-Lee; Griffiths, Julia; Lai, F. Anthony

doi:10.1093/cvr/cvp273

Cited by 36 publications

(29 citation statements)

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“…Previous reports indicated that K201 strengthens FKBP12.6 binding to RyR2 and FKBP12.6 is a requirement for K201-induced channel gating stabilization of RyR2 in myocytes (Yano et al, 2003;Wehrens et al, 2005). In vitro studies, however, suggest that K201 increasing FKBP12.6 rate of dissociation from RyRs (Blayney et al, 2010). Here, we tested if the effect of K201 on RyRs could be related to FKBP12.6 dissociation.…”

Section: Effects Of K201 On Ryrs and Sercamentioning

confidence: 96%

“…Two studies assessed the effects of K201 on the RyR isoform 1 (RyR1). In one study, K201 was found to slightly decrease or increase [ 3 H] ryanodine binding to purified and solubilized RyR1 in the absence or presence of physiologic levels of Mg 21 , respectively (Blayney et al, 2010). The other study described a K201-induced increase in SR Ca 21 release from microsomes (Almassy et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

2016

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Section: Effects Of K201 On Ryrs and Sercamentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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

2016

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“…Neonatal ventricular myocytes were obtained and cultured as described previously [9] . Briefly, myocytes were obtained and cultured in 20% FBS-DMEM culture medium with BrdU to suppress the growth of fibroblasts.…”

Section: Cell Culturementioning

confidence: 99%

“…FKBP12.6 also plays a role in the molecular mechanisms underlying severe arrhythmias and cardiac insufficiency [8] . CPVT may be the conse- [9] . FKBP12.6/12 dissociation from the binding site at RyR2 is likely due to a decrease in affinity, but this hypothesis is still controversial [10] .…”

Section: Introductionmentioning

confidence: 99%

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Zhang

Dai

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate which endothelin receptors mediated isoproterenol (ISO)-induced downregulation of FKBP12.6/12 in cardiomyocytes and study whether argirhein, a novel compound containing rhein and L-arginine that has anti-inflammatory activity, could reverse the downregulation of FKBP12.6/12 induced by ISO. Methods: Neonatal rat cardiomyocytes were incubated with ISO to downregulate FKBP12.6/12. Then the cells were treated with a selective ET A blocker (PD156707) and a ET B blocker (IRL1038), a dual ET A /ET B antagonist (CPU0213), and argirhein, respectively. FKBP12.6/12 expression was assayed by RT-PCR, Western blot, and immunocytochemistry. Results: The expression of FKBP12.6 mRNA was reduced by 37.7% (P<0.01) and 28.9% (P<0.05) relative to the control by ISO 1 and 0.1 μmol/L, respectively, but no response to ISO 0.01 μmol/L was observed in vitro. FKBP12.6/12 protein expression was reduced by 47.2% (P<0.01) and 37.8% (P<0.05) by ISO 1 and 0.1 μmol/L, respectively. This decrease was reversed significantly by PD156707, or IRL1038, and CPU0213. CPU0213 was more potent than either PD156707 or IRL-1038. Argirhein 10 µmol/L blunted the downregulation of FKBP12.6/12 by ISO, as demonstrated by the rising mRNA and protein levels and by the fluorescent density of the ISOincubated cardiomyocytes. Conclusion: In cardiomyocytes, the ISO induced downregulation of FKBP12.6/12 is modulated by both ET A and ET B . A new compound, argirein, reversed the down-regulation of FKBP12.6/12 expression in myocardial cells stimulated with ISO.

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“…Others have studied isolated RyR2 preparations and observed that not only phosphorylation at S2808, but also dephosphorylation, increased its open probability (9,11). Several groups have failed to reproduce the effect observed by Marks and colleagues (2) of PKA phosphorylation at S2808 or mutations of this site on FKBP12.6 binding (2, 10, 12, 13), but others have (14). Moreover, a recent study by the Bers group (10) reported very low FKBP12.6 concentrations in rodent cardiomyocytes, resulting in only 10%-20% of RyR2 being occupied by FKBP12.6.…”

Section: Figurementioning

confidence: 99%

Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

Eschenhagen

2010

J. Clin. Invest.

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cal for superinfection by cytomegalovirus. Science. 2010;328(5974) Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure? Thomas EschenhagenDepartment of Experimental Pharmacology and Toxicology, Cardiovascular Research Center Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, Germany.In situations of stress the heart beats faster and stronger. According to Marks and colleagues, this response is, to a large extent, the consequence of facilitated Ca 2+ release from intracellular Ca 2+ stores via ryanodine receptor 2 (RyR2), thought to be due to catecholamine-induced increases in RyR2 phosphorylation at serine 2808 (S2808). If catecholamine stimulation is sustained (for example, as occurs in heart failure), RyR2 becomes hyperphosphorylated and "leaky," leading to arrhythmias and other pathology. This "leaky RyR2 hypothesis" is highly controversial. In this issue of the JCI, Marks and colleagues report on two new mouse lines with mutations in S2808 that provide strong evidence supporting their theory. Moreover, the experiments revealed an influence of redox modifications of RyR2 that may account for some discrepancies in the field.The heart has a remarkable capacity to react to altered demand by changing the rate at which it beats and the force with which it contracts, thereby changing its output. Both the reduction of cardiac output in phases of rest and its increase in physical and emotional exercise (the fight or flight response) are essential for normal body homeostasis and long-term survival. It is not surprising therefore that cardiac rate and force are regulated at multiple levels, extrinsic and intrinsic to the heart, and in a highly complex and secured fashion. Stimulation of b 1 -adrenergic receptors by the sympathetic neurotransmitter norepinephrine induces increased production of the second messenger cAMP. cAMP directly and indirectly (via activation of PKA) induces faster depolarization in sinoatrial node cells (the cells that generate the action potentials that trigger cardiac contraction) and thus acceleration of heart rate (i.e., it has a "positive chronotropic effect") and stronger contraction (i.e., it has a "positive inotropic effect") and faster relaxation (i.e., it has a "positive lusitropic effect") in working myocytes. In chronic heart failure, one of the most frequent life-threatening diseases in Western societies, norepinephrine levels are chronically elevated, which leads to desensitization of the b-adrenergic signalling cascade and blunted responses. b-Blockers, introduced by Waagstein and colleagues in the mid 1970s, protect the heart from chronic sympathetic stimulation and provide the largest prognostic benefit for patients with chronic heart failure. Cardiac excitation-contraction couplingThe positive inotropic and lusitropic consequences of b 1 -adrenergic receptor stimulation in cardiomyocytes are explained by changes in excitation-contraction coupling, i.e., the relationship between the cardiac action potential and myofilament acti...

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A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201

Cited by 36 publications

References 58 publications

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

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

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

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A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201

Cited by 36 publications

References 58 publications

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

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

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

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Resources

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

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