title: Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression.
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 [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.
authors: Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121, USA; Department of Medicine, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors: Jong Youl
authors: JY
authors: Kim
authors: Nuri
authors: N
authors: Kim
authors: Midori A
authors: MA
authors: Yenari
authors: Wenhan
authors: W
authors: Chang