IP3R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca2＋]

Chung, Joshua; Tilūnaitė, Agne; Ladd, David; Hunt, Hilary; Soeller, Christian; Crampin, Edmund J.; Johnston, Sue; Roderick, H. Llewelyn; Rajagopal, Vijay

doi:10.1016/j.mbs.2022.108923

Cited by 7 publications

(9 citation statements)

References 45 publications

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“…IP3Rs may impart this modulatory effect on the genesis of sparks by increasing the sensitivity of RyR3 to opening by elevating the local cytoplasmic Ca 2+ . In cardiac muscle, Ca 2+ actually increases the frequency of the sparks, but leads to a reduction in amplitude [ 36 ]; however, if the free cytoplasmic Ca 2+ concentration [Ca 2+ ] i is well buffered, the opposite effect is to be expected. In DRG, local [Ca 2+ ] i is likely to also be influenced by other Ca 2+ sources such as L-type Ca 2+ channels and the Ca 2+ -release-activated Ca 2+ channel complex (STIM1-Orai1); the components of this complex are clustered into signalling nanodomains via structural proteins such as junctophilins known to exist in the DRG ER membrane [ 20 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons

Hurley,

Shah,

Sheard

et al. 2023

Cells

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Coordinated events of calcium (Ca2+) released from the endoplasmic reticulum (ER) are key second messengers in excitable cells. In pain-sensing dorsal root ganglion (DRG) neurons, these events can be observed as Ca2+ sparks, produced by a combination of ryanodine receptors (RyR) and inositol 1,4,5-triphosphate receptors (IP3R1). These microscopic signals offer the neuronal cells with a possible means of modulating the subplasmalemmal Ca2+ handling, initiating vesicular exocytosis. With super-resolution dSTORM and expansion microscopies, we visualised the nanoscale distributions of both RyR and IP3R1 that featured loosely organised clusters in the subplasmalemmal regions of cultured rat DRG somata. We adapted a novel correlative microscopy protocol to examine the nanoscale patterns of RyR and IP3R1 in the locality of each Ca2+ spark. We found that most subplasmalemmal sparks correlated with relatively small groups of RyR whilst larger sparks were often associated with larger groups of IP3R1. These data also showed spontaneous Ca2+ sparks in <30% of the subplasmalemmal cell area but consisted of both these channel species at a 3.8–5 times higher density than in nonactive regions of the cell. Taken together, these observations reveal distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca2+ released at each Ca2+ spark.

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Section: Discussionmentioning

confidence: 99%

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons

Hurley,

Shah,

Sheard

et al. 2023

Cells

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“…RyRs can sense the concentration level of Ca 2+ within SR and ER through a mechanism named ‘store overload‐induced Ca 2+ releases’ 22 . Likewise, cyclic adenosine diphosphate (ADP)‐ribose has a critical role in the activation of RyRs 22,23 …”

Section: Characteristics Of Ryanodine Receptorsmentioning

confidence: 99%

“…22 Likewise, cyclic adenosine diphosphate (ADP)-ribose has a critical role in the activation of RyRs. 22,23 There are three types of RyRs: RyR1 is mainly expressed in the skeletal muscles, RyR2 is expressed in the heart and RyR3 is mainly expressed in the brain. 24 Agonists of RyRs, including xanthine drugs, suramin and 4-chloro-m-cresol as well as cyclic ADP-ribose, act as an endogenous activator of RyRs.…”

Section: Characteristics Of Ryanodine Receptorsmentioning

confidence: 99%

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

Alkazmi

Al-Kuraishy

Al-Gareeb

et al. 2023

Clin Exp Pharma Physio

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Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca 2+ release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of malignant hyperthermia. RyRs are highly expressed in immune cells and are involved in different viral infections, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), because Ca 2+ is necessary for viral replication, maturation and release. DTN can inhibit the proliferation of SARS-CoV-2, indicating its potential role in reducing entry and pathogenesis of SARS-CoV-2. DTN may increase clearance of SARS-CoV-2 and promote coronavirus disease 2019 (COVID-19) recovery by shortening the period of infection. DTN inhibits N-methyl-D-aspartate (NMDA) mediated platelets aggregations and thrombosis. Therefore, DTN may inhibit thrombosis and coagulopathy in COVID-19 through suppression of platelet NMDA receptors. Moreover, DTN has a neuroprotective effect against SARS-CoV-2 infection-induced brain injury through modulation of NMDA receptors, which are involved in excitotoxicity, neuronal injury and the development of neuropsychiatric disorders. In conclusion, DTN by inhibiting RyRs may attenuate inflammatory disorders in SARS-CoV-2 infection and associated cardio-pulmonary complications. Therefore, DNT could be a promising drug therapy against COVID-19. Preclinical and clinical studies are warranted in this regards.

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“…The unequivocal fact is that Ca 2+ plays a critical role in cardiac cells, coupling electrical excitation to mechanical contraction (excitation–contraction coupling, ECC) with each heartbeat [ 25 ]. The sarcoplasmic reticulum is a high-capacity reservoir of intracellular Ca 2+ required for the regulation of muscle activity [ 26 , 27 ] that is mediated by the cooperation of two essential Ca 2+ -release channels, inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) [ 28 ], and by the activity of SR/ER Ca 2+ -ATPase (SERCA2a), which is responsible for the reuptake of intracellular Ca 2+ into SR, thus achieving ECC [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, they possess distinct physiological and pharmacological profiles [ 28 ]. While RyR is the primary Ca 2+ channel responsible for generating the cell-wide Ca 2+ transients during ECC in the heart, the release of Ca 2+ via IP3Rs can elicit ECC-modulating effects [ 25 ], depending on its location. Aging attenuates Ca 2+ transients, which are significantly prolonged [ 31 ] due to reduced SERCA2a expression and ROS-induced over-activation of RyRs [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Age-Dependent Changes in Calcium Regulation after Myocardial Ischemia–Reperfusion Injury

et al. 2023

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During aging, heart structure and function gradually deteriorate, which subsequently increases susceptibility to ischemia–reperfusion (IR). Maintenance of Ca2+ homeostasis is critical for cardiac contractility. We used Langendorff’s model to monitor the susceptibility of aging (6-, 15-, and 24-month-old) hearts to IR, with a specific focus on Ca2+-handling proteins. IR, but not aging itself, triggered left ventricular changes when the maximum rate of pressure development decreased in 24-month-olds, and the maximum rate of relaxation was most affected in 6-month-old hearts. Aging caused a deprivation of Ca2+-ATPase (SERCA2a), Na+/Ca2+ exchanger, mitochondrial Ca2+ uniporter, and ryanodine receptor contents. IR-induced damage to ryanodine receptor stimulates Ca2+ leakage in 6-month-old hearts and elevated phospholamban (PLN)-to-SERCA2a ratio can slow down Ca2+ reuptake seen at 2–5 μM Ca2+. Total and monomeric PLN mirrored the response of overexpressed SERCA2a after IR in 24-month-old hearts, resulting in stable Ca2+-ATPase activity. Upregulated PLN accelerated inhibition of Ca2+-ATPase activity at low free Ca2+ in 15-month-old after IR, and reduced SERCA2a content subsequently impairs the Ca2+-sequestering capacity. In conclusion, our study suggests that aging is associated with a significant decrease in the abundance and function of Ca2+-handling proteins. However, the IR-induced damage was not increased during aging.

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IP3R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca2＋]

Cited by 7 publications

References 45 publications

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

Age-Dependent Changes in Calcium Regulation after Myocardial Ischemia–Reperfusion Injury

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