Ryanodine receptor isoforms in excitation-contraction coupling

Ogawa, Yu

doi:10.1016/s0065-227x(99)90003-5

Cited by 25 publications

(33 citation statements)

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“…Our results show an increase in two types of RyR. Both RyR2 [predominantly found in heart and some expression in brain (17)] and RyR3 [ubiquitous expression (17)] are associated with lower activation thresholds compared with RyR1 (18). It is conceivable that an increase in both of these RyR isoforms in systemic VSM could translate into the observed altered intracellular Ca 2ϩ handling during hypoxia and may contribute to the loss of hypoxic vasorelaxation.…”

Section: Discussionmentioning

confidence: 65%

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Thorne

Rutgeerts

2003

American Journal of Physiology-Cell Physiology

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. Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor. Am J Physiol Cell Physiol 284: C999-C1005, 2003. First published December 11, 2002 10.1152/ajpcell.00158.2002.-Organ culture specifically inhibits vasorelaxation to acute hypoxia and preferentially decreases specific voltage-dependent K ϩ channel expression over other K ϩ and Ca 2ϩ channel subtypes. To isolate further potential oxygen-sensing mechanisms correlated with altered gene expression, we performed differential display analysis on RNA isolated from control and cultured coronary arterial rings. We hypothesize that organ culture results in altered gene expression important for vascular smooth muscle contractility important to the mechanism of hypoxia-induced relaxation. Our results indicate a milieu of changes suggesting both up-and downregulation of several genes. The altered expression pattern of two positive clones was verified by Northern analysis. Subsequent screening of a porcine cDNA library indicated homology to the ryanodine receptor (RyR). RT-PCR using specific primers to the three subtypes of RyR shows an upregulation of RyR2 and RyR3 after organ culture. Additionally, the caffeine-and/or ryanodine-sensitive intracellular Ca 2ϩ store was significantly more responsive to caffeine activation after organ culture. Our data indicate that organ culture increases expression of specific RyR subtypes and inhibits hypoxic vasorelaxation. Importantly, ryanodine blunted hypoxic relaxation in control coronary arteries, suggesting that upregulated RyR might play a novel role in altered intracellular Ca 2ϩ handling during hypoxia. ryanodine receptor; vascular smooth muscle; hypoxia A DECREASE IN OXYGEN TENSION (PO 2 ), or hypoxia, modulates coronary, and most systemic, arterial tone, causing a vasodilation to maintain delivery of adequate oxygen to the heart and other organs. The mechanism(s) by which systemic vascular smooth muscle (VSM) senses these changes in PO 2 remains unclear. Common theories include the modulation of ion channel function, an acute decrease in available ATP necessary for force maintenance, direct regulation of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), and modulation of Ca 2ϩ sensitivity (6,8,9,19). We have shown that these theories cannot completely account for the hypoxiainduced relaxation of porcine coronary arteries (20).Additionally, considerable attention has been given to small heme-containing proteins as the oxygen sensor where an PO 2 -dependent change in redox status may transduce the appropriate response (12,14,15).In a recent investigation, we demonstrate the specific inhibition of relaxation to acute hypoxia after organ culture of porcine coronary arteries (25). Organ culture of VSM is reported to cause changes in [Ca 2ϩ ] i handling (4, 7) and has been associated with altered gene expression (21). Chronic hypoxia leads to the regulation of several hypoxia-inducible genes that modulate long-term responses to decreases in PO 2 (1,13,22). It is conceiva...

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Section: Discussionmentioning

confidence: 65%

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Thorne

Rutgeerts

2003

American Journal of Physiology-Cell Physiology

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“…However, our results do not exclude the possibility that ryanodine-insensitive Ca 2ϩ stores in the postsynaptic cell are necessary for LTD. channel (VGCC) has been shown to be the dominant mechanism for providing RyRs with this trigger source of Ca 2ϩ (Ogawa et al, 1999). However, additional sources, including influx through low voltage-activated T-type Ca 2ϩ channels, have been implicated under certain situations (Ogawa et al, 1999). To test what mechanisms may be at work in CA3-CA3 synapses during the induction of LTD, we repeated our paired whole-cell recording induction protocol with the L-type VGCC antagonist nitrendipine present in the bath solution.…”

Section: Nmdar-dependent Ltd Is Present At Ca3-ca3 Synapsesmentioning

confidence: 99%

Calcium Release from Presynaptic Ryanodine-Sensitive Stores Is Required for Long-Term Depression at Hippocampal CA3-CA3 Pyramidal Neuron Synapses

Unni¹,

Zakharenko²,

Zablow³

et al. 2004

J. Neurosci.

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Although Ca2ϩ release from internal stores has been proposed to be important for the induction of long-term synaptic plasticity, the importance of Ca 2ϩ stores localized in presynaptic terminals remains unclear. Here, we have selectively applied pharmacological antagonists to either the presynaptic or postsynaptic cell in paired whole-cell recordings from hippocampal CA3 pyramidal neurons in slice culture. We demonstrate directly the necessary role of presynaptic, but not postsynaptic, ryanodine-sensitive Ca 2ϩ stores in the induction of NMDA receptor (NMDAR)-dependent long-term depression (LTD). Using two-photon laser scanning microscopy, we further find that release from the ryanodine-sensitive stores during prolonged synaptic stimulation generates a slowly rising Ca 2ϩ signal in the presynaptic terminal that is required for the induction of LTD. Moreover, this form of LTD has a significant presynaptic component of expression because it causes a marked decrease in the rate of release from CA3 neuron presynaptic terminals of FM 1-43, a fluorescent probe of synaptic vesicle cycling. Thus, Ca 2ϩ release from presynaptic ryanodine-sensitive stores is critical in the induction of a presynaptic component of NMDAR-dependent LTD.

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“…Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2,3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4).…”

mentioning

confidence: 99%

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.calcium channel | heart failure | excitation-contraction coupling | PKA | casein kinase II E xcitation-contraction (EC) coupling in the heart is initiated by L-type calcium (Ca 2+ ) currents conducted by voltagegated calcium 1.2 (Ca V 1.2) channels that are activated by membrane depolarization (1). Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2, 3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4). SERCA activity is controlled by the inhibitor protein phospholamban (PLB), which is phosphorylated by PKA to release its inhibition of SERCA activity (4). The force and rate of cardiac contractions are critically dependent on the amplitude and kinetics of the Ca 2+ signal generated by Ca V 1.2 channels and RyR2 (1). In the fight-or-flight response, a marked increase in the beating rate and force of contraction of the heart is triggered by activation of the sympathetic nervous system and stimulation of the β-adrenergic signaling p...

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Ryanodine receptor isoforms in excitation-contraction coupling

Cited by 25 publications

References 0 publications

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Calcium Release from Presynaptic Ryanodine-Sensitive Stores Is Required for Long-Term Depression at Hippocampal CA3-CA3 Pyramidal Neuron Synapses

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

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Ryanodine receptor isoforms in excitation-contraction coupling

Cited by 25 publications

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Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

Calcium Release from Presynaptic Ryanodine-Sensitive Stores Is Required for Long-Term Depression at Hippocampal CA3-CA3 Pyramidal Neuron Synapses

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

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Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure