title: Somatostatin receptor sst2 reduces Akt activity and aggravates hypoxic/ischemic death in cerebral cortical neurons.
abstract: It is established that growth factors support neuronal survival through the phosphoinositide 3-kinase (PI3K)/Akt pathway but little is known about factors that inhibit Akt signaling in neurons. Given that the sst2 type somatostatin receptor exerts pro-apoptotic effects in tumor cells by inhibiting PI3K/Akt, we examined whether neuronal sst2 has similar effects. In primary cortical cultures heterozygously expressing a sst2 knockout/lacZ knockin allele, beta-galactosidase staining revealed expression of the sst2 gene in the vast majority of the cultured neurons. Somatostatin was identified in a subpopulation of neurons by immunocytochemistry. Immunoblots showed a strong reduction of Akt phosphorylation at S473 in wild type cultures undergoing stimulation with the sst2 agonist BIM-23244. While the sst2 agonist did not cause neuronal death under control conditions, it promoted hypoxic/ischemic neuronal death in cortical cultures subjected to oxygen/glucose deprivation. Treatment of wild type cultures with the sst2 antagonist BIM-23627 and homozygous deletion of the sst2 gene were protective in this paradigm, suggesting that endogenous somatostatin signals through sst2 during hypoxia/ischemia. In fact, examination of sst2 phosphorylation and sst2 internalization provided evidence for sst2 activation in neurons subjected to oxygen/glucose deprivation. Thus, somatostatin acts as a sensor of hypoxia/ischemia, inhibits Akt activity through sst2 and aggravates hypoxic/ischemic neuronal death. sst2-selective antagonists are proposed as neuroprotectants in stroke.
authors.affiliation: Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany. Electronic address: Ralf.Stumm@med.uni-jena.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Stumm
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: C423390:BIM-23244; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Apoptosis; BSS; DIV; Ischemia; NG; Neuroprotection; OGD; PKB; Preconditioning; Somatostatin; Stroke; balanced salt solution; days in vitro; normoxia/glucose; oxygen/glucose deprivation