Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression
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.
KeywordsCalcium-sensing receptor Global cerebral ischemia Hypothermia Neuroprotection
- 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar