Skip to main content

Advertisement

SpringerLink
Log in

Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Hypothermia improves neurological outcome from cardiac arrest. The mechanisms of protection are multifold, but identifying some may be useful in exploring potential therapeutic targets. The extracellular calcium-sensing receptor (CaSR) was originally found in parathyroid cells in which the receptor senses minute changes in extracellular [Ca2+] and promotes Ca2+ influx and intracellular Ca2+ release. The CaSR is broadly expressed in the CNS and colocalized with the inhibitory γ-aminobutyric acid-B receptor 1 (GABA-B-R1). In hippocampal neurons, GABA-B-R1 heterodimerizes with CaSR and suppresses CaSR expression. To study the interplay between these two receptors in the development of ischemic cell death and neuroprotection by hypothermia, we subjected C57/BL6 mice to global cerebral ischemia by performing bilateral carotid artery occlusion (10 min) followed by reperfusion for 1–3 days with or without therapeutic hypothermia (33°C for 3 h at the onset of reperfusion). Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry showed that forebrain ischemia increased CaSR expression, decreased GABA-B-R1 expression, and promoted cell death. These changes were particularly evident in hippocampal neurons and could be reversed by mild hypothermia. The induction of CaSR, along with reciprocal decreases in GABA-B-R1 expression, may together potentiate ischemic neuronal death, suggesting a new therapeutic target for treatment of ischemic brain injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Menon B, Shorvon SD. Ischaemic stroke in adults and epilepsy. Epilepsy Res. 2009;87(1):1–11.

    Article  PubMed  Google Scholar 

  2. Ikonomidou C, Stefovska V, Turski L. Neuronal death enhanced by N-methyl-D-aspartate antagonists. Proc Natl Acad Sci USA. 2000;97(23):12885–90.

    Article  PubMed  CAS  Google Scholar 

  3. Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 2002;1(6):383–6.

    Article  PubMed  CAS  Google Scholar 

  4. Vollenweider F, Bendfeldt K, Maetzler W, Otten U, Nitsch C. GABA(B) receptor expression and cellular localization in gerbil hippocampus after transient global ischemia. Neurosci Lett. 2006;395(2):118–23.

    Article  PubMed  CAS  Google Scholar 

  5. Costa C, Leone G, Saulle E, Pisani F, Bernardi G, Calabresi P. Coactivation of GABA(A) and GABA(B) receptor results in neuroprotection during in vitro ischemia. Stroke. 2004;35(2):596–600.

    Article  PubMed  CAS  Google Scholar 

  6. Zhou C, Li C, Yu HM, Zhang F, Han D, Zhang GY. Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia. J Neurosci Res. 2008;86(13):2973–83.

    Article  PubMed  CAS  Google Scholar 

  7. Epsztein J, Ben-Ari Y, Represa A, Crepel V. Late-onset epileptogenesis and seizure genesis: lessons from models of cerebral ischemia. Neuroscientist. 2008;14(1):78–90.

    Article  PubMed  CAS  Google Scholar 

  8. Jackson-Friedman C, Lyden PD, Nunez S, Jin A, Zweifler R. High dose baclofen is neuroprotective but also causes intracerebral hemorrhage: a quantal bioassay study using the intraluminal suture occlusion method. Exp Neurol. 1997;147(2):346–52.

    Article  PubMed  CAS  Google Scholar 

  9. Canaff L, Zhou X, Hendy GN. The proinflammatory cytokine, interleukin-6, up-regulates calcium-sensing receptor gene transcription via Stat1/3 and Sp1/3. J Biol Chem. 2008;283(20):13586–600.

    Article  PubMed  CAS  Google Scholar 

  10. Kobuchi S, Shintani T, Sugiura T, Tanaka R, Suzuki R, Tsutsui H, et al. Renoprotective effects of gamma-aminobutyric acid on ischemia/reperfusion-induced renal injury in rats. Eur J Pharmacol. 2009;623(1–3):113–8.

    Article  PubMed  CAS  Google Scholar 

  11. Hypothermia after Cardiac Arrest Study Group T. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56.

    Article  Google Scholar 

  12. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63.

    Article  PubMed  Google Scholar 

  13. Azzopardi D, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349–58.

    Article  PubMed  CAS  Google Scholar 

  14. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663–70.

    PubMed  Google Scholar 

  15. Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA, et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002;110(2 Pt 1):377–85.

    Article  PubMed  Google Scholar 

  16. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.

    Article  PubMed  CAS  Google Scholar 

  17. Yano S, Brown EM, Chattopadhyay N. Calcium-sensing receptor in the brain. Cell Calcium. 2004;35(3):257–64.

    Article  PubMed  CAS  Google Scholar 

  18. Vizard TN, O'Keeffe GW, Gutierrez H, Kos CH, Riccardi D, Davies AM. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat Neurosci. 2008;11(3):285–91.

    Article  PubMed  CAS  Google Scholar 

  19. Chattopadhyay N, Jeong KH, Yano S, Huang S, Pang JL, Ren X, et al. Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice. Am J Physiol Endocrinol Metab. 2007;292(2):E523–32.

    Article  PubMed  CAS  Google Scholar 

  20. Bandyopadhyay S, Jeong KH, Hansen JT, Vassilev PM, Brown EM, Chattopadhyay N. Calcium-sensing receptor stimulates secretion of an interferon-gamma-induced monokine (CXCL10) and monocyte chemoattractant protein-3 in immortalized GnRH neurons. J Neurosci Res. 2007;85(4):882–95.

    Article  PubMed  CAS  Google Scholar 

  21. Washburn DL, Smith PM, Ferguson AV. Control of neuronal excitability by an ion-sensing receptor (correction of anion-sensing). Eur J Neurosci. 1999;11(6):1947–54.

    Article  PubMed  CAS  Google Scholar 

  22. Ye CP, Yamaguchi T, Chattopadhyay N, Sanders JL, Vassilev PM, Brown EM. Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR. Bone. 2000;27(1):21–7.

    Article  PubMed  CAS  Google Scholar 

  23. Chattopadhyay N, Ye C, Yamaguchi T, Nakai M, Kifor O, Vassilev PM, et al. The extracellular calcium-sensing receptor is expressed in rat microglia and modulates an outward K+ channel. J Neurochem. 1999;72(5):1915–22.

    Article  PubMed  CAS  Google Scholar 

  24. Chattopadhyay N, Ye CP, Yamaguchi T, Vassilev PM, Brown EM. Evidence for extracellular calcium-sensing receptor mediated opening of an outward K+ channel in a human astrocytoma cell line (U87). Glia. 1999;26(1):64–72.

    Article  PubMed  CAS  Google Scholar 

  25. Chang W, Tu C, Cheng Z, Rodriguez L, Chen TH, Gassmann M, et al. Complex formation with the type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. J Biol Chem. 2007;282(34):25030–40.

    Article  PubMed  CAS  Google Scholar 

  26. Webster CM, Kelly S, Koike MA, Chock VY, Giffard RG, Yenari MA. Inflammation and NFkappaB activation is decreased by hypothermia following global cerebral ischemia. Neurobiol Dis. 2009;33(2):301–12.

    Article  PubMed  CAS  Google Scholar 

  27. Yenari MA, Onley D, Hedehus M, de Crespigny A, Sun GH, Moseley ME, et al. Diffusion- and perfusion-weighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under conditions of mild hypothermia. Brain Res. 2000;885(2):208–19.

    Article  PubMed  CAS  Google Scholar 

  28. Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D. Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera. J Bone Miner Res. 1998;13(4):570–80.

    Article  PubMed  CAS  Google Scholar 

  29. Guo J, Li HZ, Zhang WH, Wang LC, Wang LN, Zhang L, et al. Increased expression of calcium-sensing receptors induced by ox-LDL amplifies apoptosis of cardiomyocytes during simulated ischaemia–reperfusion. Clin Exp Pharmacol Physiol. 2010;37(3):e128–35.

    Article  PubMed  CAS  Google Scholar 

  30. Jiang CM, Han LP, Li HZ, Qu YB, Zhang ZR, Wang R, et al. Calcium-sensing receptors induce apoptosis in cultured neonatal rat ventricular cardiomyocytes during simulated ischemia/reperfusion. Cell Biol Int. 2008;32(7):792–800.

    Article  PubMed  CAS  Google Scholar 

  31. Sun J, Murphy E. Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol. 2010;299(5):H1309–17.

    Article  PubMed  CAS  Google Scholar 

  32. Gilby KL, Sydserff SG, Robertson HA. Differential neuroprotective effects for three GABA-potentiating compounds in a model of hypoxia-ischemia. Brain Res. 2005;1035(2):196–205.

    Article  PubMed  CAS  Google Scholar 

  33. Wahlgren NG, Ranasinha KW, Rosolacci T, Franke CL, van Erven PM, Ashwood T, et al. Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke. 1999;30(1):21–8.

    PubMed  CAS  Google Scholar 

  34. Lyden P, Shuaib A, Ng K, Levin K, Atkinson RP, Rajput A, et al. Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke. 2002;33(1):122–8.

    Article  PubMed  CAS  Google Scholar 

  35. Munoz A, Arellano JI, DeFelipe J. GABABR1 receptor protein expression in human mesial temporal cortex: changes in temporal lobe epilepsy. J Comp Neurol. 2002;449(2):166–79.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from NIH NIA (R01 AG21353 to WC), NINDS (R01 NS40516, P50 NS014543 to MAY), and the Department of Defense (MAY, WC). This work was also supported by the Department of Veterans Affairs.

Author information

Authors and Affiliations

  1. Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA, 94121, USA

    Jong Youl Kim, Nuri Kim & Midori A. Yenari

  2. Department of Medicine, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, CA, 94121, USA

    Jong Youl Kim & Wenhan Chang

Authors
  1. Jong Youl Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nuri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Midori A. Yenari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenhan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Midori A. Yenari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J.Y., Kim, N., Yenari, M.A. et al. Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression. Transl. Stroke Res. 2, 195–201 (2011). https://doi.org/10.1007/s12975-011-0082-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-011-0082-4

Keywords

Search

Navigation