Effect of inositol 1, 4, 5-trisphosphate receptor dependent Ca2+ release in atrial fibrillation

0
0
0

Effect of inositol 1, 4, 5-trisphosphate receptor dependent Ca2+ release in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder globally, affecting over 33 million people and raising the risk of stroke, heart failure, and premature death. While its roots are multifaceted, a growing body of research identifies disrupted calcium (Ca²⁺) balance in the heart’s upper chambers (atria) as a key driver. Central to this balance are inositol 1,4,5-trisphosphate receptors (IP3Rs)—proteins that control Ca²⁺ release from intracellular storage structures called the sarcoplasmic reticulum (SR). A 2020 study by Lu Han, Zi-Rong Xia, and Ju-Xiang Li from the Department of Cardiovascular Medicine at the Second Affiliated Hospital of Nanchang University explores how IP3R-dependent Ca²⁺ release fuels AF development, offering critical insights into potential treatments.

IP3Rs: Gatekeepers of Ca²⁺ Homeostasis

IP3Rs act as molecular “gates” on the SR, releasing Ca²⁺ only when two signals are present: the molecule inositol 1,4,5-trisphosphate (IP3) and a small amount of Ca²⁺ itself. Clustered IP3Rs (groups of receptors) are far more active than isolated ones, creating a “cooperative” effect that amplifies Ca²⁺ release.

When IP3Rs are overexpressed or overactive, too much Ca²⁺ leaks from the SR. This triggers the sodium-calcium exchanger (NCX)—a protein that swaps Ca²⁺ for sodium (Na⁺)—leading to Na⁺ overload in atrial cells. Excess Na⁺ lengthens the heart’s electrical “action potential” and extends the refractory period (when cells can’t reactivate), creating a stable environment for AF. It also causes early and delayed afterdepolarizations—abnormal extra electrical signals that directly trigger arrhythmias.

Crucially, studies in IP3R2-knockout mice (missing the IP3R2 subtype) found AF was completely abolished, proving IP3Rs are essential to AF development.

Atrial Remodeling: The “Substrate” for AF

AF doesn’t just disrupt heart rhythm—it reshapes the atria themselves. Atrial remodeling—defined by fibrosis (scar tissue), enlargement, and fatty infiltration—is often called the “hallmark of the arrhythmogenic substrate.” Scar tissue creates uneven electrical conduction, allowing abnormal “re-entry” loops (electrical signals that circle back and re-excite cells) to sustain AF.

Research confirms remodeling is present in both paroxysmal (intermittent) and permanent AF. In IP3R-deficient models, collagen I (a key fibrosis marker) was reduced, linking IP3R activity to scar formation. The study also notes that IP3R-mediated electrical remodeling (e.g., longer action potentials) drives structural remodeling by increasing afterload (the heart’s pumping resistance) and peripheral tension.

Inflammation: A Pro-AF Signal

Inflammation is a major AF trigger—especially after heart surgery, where elevated levels of C-reactive protein (CRP), interleukin-2 (IL-2), and IL-6 predict post-operative AF. Atrial inflammation and fibrosis share overlapping signaling pathways, creating a “vicious cycle” that worsens conduction heterogeneity.

IP3Rs play a direct role in this cycle: their activation promotes the release of pro-inflammatory cytokines like IL-6, IL-8, and macrophage inflammatory protein-1β. Conversely, inhibiting IP3Rs with a compound called 2-aminoethoxydiphenyl borate reduces these cytokines. This suggests IP3R inhibitors could block the arrhythmic effects of inflammation, offering a new way to prevent AF in high-risk patients (e.g., post-surgery).

Oxidative Stress: Fueling the Fire

Oxidative stress—an imbalance between harmful oxidants (like reactive oxygen species, ROS) and protective antioxidants—damages cells and disrupts heart function. In the atria, ROS is far more effective at activating IP3Rs than in the ventricles, creating a atria-specific vulnerability.

IP3R-mediated Ca²⁺ release also opens mitochondrial permeability transition pores (mPTPs)—channels in mitochondria that leak ROS and trigger cell death. This creates a feedback loop: oxidative stress activates IP3Rs, which release more Ca²⁺, open more mPTPs, and generate more ROS. The result is impaired diastolic function (the heart’s relaxation phase) and accelerated AF progression.

Pre-treating cells with N-acetylcysteine—an IP3R inhibitor and antioxidant—blocks IP3R1-mediated Ca²⁺ overload, proving that targeting IP3Rs can break this cycle.

Protein kinases (enzymes that modify proteins) add another layer of regulation:

  • PKA (protein kinase A) phosphorylates IP3R1 and IP3R2, enhancing Ca²⁺ release.
  • PKC (protein kinase C) uses the PLC-PKC-IP3R pathway to increase intracellular Ca²⁺.
  • PKG (protein kinase G) suppresses IP3R1 activity, reducing Ca²⁺ oscillations.

These differences mean different kinase inhibitors could be used to “fine-tune” IP3R activity for AF treatment.

Apoptosis: Cell Death and Rhythm Chaos

Atrial remodeling, inflammation, and oxidative stress all converge on cell apoptosis (programmed cell death). When IP3Rs leak too much Ca²⁺, mitochondria take up excess Ca²⁺, deplete ATP (energy), and trigger apoptosis.

Proteins from the Bcl-2 family—key regulators of apoptosis—directly interact with IP3Rs:

  • Bax/Bak (pro-apoptotic) reduce Ca²⁺ leakage by regulating IP3R1 phosphorylation.
  • Bcl-2 (anti-apoptotic) forms a complex with IP3Rs to control mitochondrial Ca²⁺ uptake and ATP metabolism.

Mutations in Bcl-2 (e.g., lysine 17) abolish its ability to inhibit IP3Rs, leading to uncontrolled Ca²⁺ leakage and cell death. This disrupts atrial tissue structure and electrical conduction, further worsening AF.

Mutations and Interacting Proteins: Uncovering the Network

Genetic mutations in IP3Rs and related proteins directly link to AF:

  • The P1059L mutation in the IP3R regulatory domain increases binding to IP3, amplifying Ca²⁺ signals.
  • IP3R1/IP3R2 double-knockout mice die in utero due to severe cardiac defects (thin heart walls, missing atrioventricular canals), highlighting IP3Rs’ role in normal heart development.
  • A D1790G mutation in the Na⁺ channel Nav1.5 co-localizes with calcium/calmodulin-dependent protein kinase II (CaMKII), disrupting IP3R1 function and causing Na⁺/Ca²⁺ overload—key drivers of arrhythmias.

IP3Rs also interact with other proteins to regulate Ca²⁺ homeostasis:

  • RyR2 (ryanodine receptor 2): Co-localizes with IP3Rs in atrial cells, creating a “cross-talk” that modulates Ca²⁺ release.
  • TRPC3 (transient receptor potential canonical 3): Forms a complex with IP3R1 and NCX to mediate Ca²⁺ overload during inflammation. TRPC3-knockout mice are protected from angiotensin II-induced AF.
  • STIM/ORAI1: When the SR’s Ca²⁺ stores are depleted, STIM (stromal interaction molecule) binds to ORAI1 (a Ca²⁺ channel) to trigger store-operated calcium entry (SOCE)—a process that refills Ca²⁺ stores. IP3R-mediated Ca²⁺ release activates STIM, creating a feedback loop that controls SOCE activity.

Why This Matters for AF Treatment

The study’s biggest takeaway? IP3Rs are not just bystanders—they are central to almost every pathway that drives AF:

  • Ca²⁺ dysregulation from IP3Rs triggers electrical and structural remodeling.
  • Inflammation and oxidative stress are amplified by IP3R activity.
  • Apoptosis and genetic mutations directly involve IP3Rs.

By targeting IP3Rs or their downstream pathways, researchers could develop therapies that address AF’s root causes—rather than just its symptoms. For example:

  • IP3R inhibitors could reduce Ca²⁺ leakage and inflammation.
  • Kinase-specific drugs (e.g., PKG activators) could suppress overactive IP3Rs.
  • Gene therapies could correct IP3R mutations linked to AF.

The original study was published in the Chinese Medical Journal (2020;133:1732–1734) by Lu Han, Zi-Rong Xia, and Ju-Xiang Li from the Second Affiliated Hospital of Nanchang University. It was funded by the National Natural Science Foundation of China (No. 81200132), the Natural Science Foundation of Jiangxi (No. 20152ACB20025), and the Project of Science and Technology of Jiangxi (No. 20151BBG70166).

References

  1. Piegari E, Villarruel C, Ponce DS. Changes in Ca²⁺ removal can mask the effects of geometry during IP3R mediated Ca²⁺ signals. Front Physiol 2019;10:1–31. https://doi.org/10.3389/fphys.2019.00964
  2. Navid P, Pichard KH. Structural basis for the regulation of inositol trisphosphate receptors by Ca²⁺ and IP3. Nat Struct Mol Biol 2018;25:660–668. https://doi.org/10.1038/s41594-018-0089-6
  3. Li X, Zima AV, Sheikh F, Blatter LA, Chen J. Endothelin-1-induced arrhythmogenic Ca²⁺ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice. Circ Res 2005;96:1274–1281. https://doi.org/10.1161/01.RES.0000172556.05576.4c
  4. Xie A, Zhou A, Liu H, Shi G, Liu M, Boheler KR, et al. Mitochondrial Ca²⁺ flux modulates spontaneous electrical activity in ventricular cardiomyocytes. PLoS One 2018;13:1–17. https://doi.org/10.1371/journal.pone.0200448
  5. Han L, Tang Y, Li S, Wu Y, Chen X, Wu Q, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J Cell Mol Med 2020;24:488–510. https://doi.org/10.1111/jcmm.14757
  6. Zhang B, Li M, Yang W, Loor JJ, Wang S, Zhao Y, et al. Orai calcium release-activated calcium modulator 1 (ORAI1) plays a role in endoplasmic reticulum stress in bovine mammary epithelial cells challenged with physiological levels of ketone bodies. J Dairy Sci 2020;S0022-0302:30190–30199. https://doi.org/10.3168/jds.2019-17422
  7. Nomani H, Saei S, Johnston TP, Sahebkar A, Mohammadpour AH. The efficacy of anti-inflammatory agents in the prevention of atrial fibrillation recurrences. Curr Med Chem 2020;5:1–23. https://doi.org/10.2174/1389450121666200302095103
  8. Zhu X, Niu Z, Ye Y, Xia L, Chen Q, Feng Y. Endometrium cytokine profiles are altered following ovarian stimulation but almost not in subsequent hormone replacement cycles. Cytokine 2019;114:6–10. https://doi.org/10.1016/j.cyto.2018.11.002
  9. Purvi M, Michael S, Javier AN, David PB. Calcium channel Orai 1 promotes lymphocyte IL-17 expression and progressive kidney injury. J Clin Invest 2019;129:4951–4961. https://doi.org/10.1172/JCI126108
  10. Qin J, Peng ZZ, Li Q, Wen R, Tao LJ. Renal fibrosis and mitochondrial damage. Chin Med J 2018;131:2769–2772. https://doi.org/10.4103/0366-6999.245272
  11. Taylor CW. Regulation of IP3 receptors by cyclic AMP. Cell Calcium 2017;63:48–52. https://doi.org/10.1016/j.ceca.2016.10.005
  12. Atakpa P, van Marrewijk LM, Apta-Smith M, Chakraborty S, Taylor CW. GPN does not release lysosomal Ca²⁺, but evokes ER Ca²⁺ release by increasing cytosolic pH independent of cathepsin C. J Cell Sci 2019;1:1–45. https://doi.org/10.1242/jcs.223883
  13. Zhao P, Tian D, Song G, Ming Q, Liu J, Shen J, et al. Neferine promotes GLUT4 expression and fusion with the plasma membrane to induce glucose uptake in L6 cells. Front Pharmacol 2019;10:1–22. https://doi.org/10.3389/fphar.2019.00999
  14. Murthy KS, Zhou H. Selective phosphorylation of the IP3 R-I in vivo by cGMP-dependent protein kinase in smooth muscle. Physiol Gastrointest Liver Physiol 2003;284:221–230. https://doi.org/10.1152/ajpgi.00401.2002
  15. Ando H, Kawaai K, Bonneau B, Mikoshiba K. Remodeling of Ca²⁺ signaling in cancer: regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors. Adv Biol Regul 2018;68:64–76. https://doi.org/10.1016/j.jbior.2017.12.001
  16. Cui G, Li Y, Ding K, Hao S, Wang J, Zhang Z. Attribution of Bax and mitochondrial permeability transition pore on cantharidin-induced apoptosis of Sf9 cells. Pestic Biochem Physiol 2017;142:91–101. https://doi.org/10.1016/j.pestbp.2017.01.010
  17. Lopez JR, Kolster J, Uryash A, Estève E, Altamirano F, Adams JA. Dysregulation of intracellular Ca²⁺ in dystrophic cortical and hippocampal neurons. Mol Neurobiol 2018;55:603–618. https://doi.org/10.1007/s12035-016-0311-7
  18. Fuping Z, Wuping L, Linhua W, Chengxi P, Fuqiang Z, Yi Z, et al. Tao-Hong-Si-Wu decoction reduces ischemia reperfusion rat myoblast cells calcium overloading and inflammation through the Wnt/IP3R/CaMKII pathway. J Cell Biochem 2019;120:13095–13106. https://doi.org/10.1002/jcb.28582
  19. Joseph SK, Booth DM, Young MP, Hajnóczky G. Redox regulation of ER and mitochondrial Ca²⁺ signaling in cell survival and death. Cell Calcium 2019;79:89–97. https://doi.org/10.1016/j.ceca.2019.02.006
  20. Yu Y, Zhou CH, Yao YT, Li LH. Downregulation of Na⁺/Ca²⁺ exchanger isoform 1 protects isolated hearts by sevoflurane postconditioning but not by delayed remote ischemic preconditioning in rats. Chin Med J 2018;131:756. https://doi.org/10.4103/0366-6999.226907
  21. Taylor CW, Machaca K. IP3 receptors and store-operated Ca²⁺ entry: a license to fill. Curr Opin Cell Biol 2019;57:1–7. https://doi.org/10.1016/j.ceb.2018.10.001
  22. Han L, Xia ZR, Li JX. Effect of inositol 1, 4, 5-trisphosphate receptor dependent Ca²⁺ release in atrial fibrillation. Chin Med J 2020;133:1732–1734. https://doi.org/10.1097/CM9.00000000000008

Was this helpful?

0 / 0