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 [Ca(2+)] and promotes Ca(2+) influx and intracellular Ca(2+) 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.