Somatostatin Receptor 2 Is Activated in Cortical Neurons and Contributes to Neurodegeneration after Focal Ischemia

Abstract

Somatostatin receptor 2 (SSTR2) mediates neuromodulatory signals of somatostatin and cortistatin in the cerebral cortex. Recently, SSTR2 has been shown to enhance conserved death ligand-and mitochondria-mediated apoptotic pathways in non-neuronal cells. Whether somatostatin receptors are activated in cerebrocortical neurons and contribute to neurodegeneration after experimental focal ischemia was unknown until now. Here we examined internalization of SSTR2 in a rat model of middle cerebral artery occlusion (MCAO) by confocal microscopy. At 3 and 6 hr after MCAO, SSTR2 was internalized excessively in cerebrocortical neurons adjacent to the infarct, which was prevented by intracerebroventricular application of the SSTR2-selective antagonist BIM-23627. SSTR2 internalization was associated with a transient depletion of somatostatin from axonal terminals and increased expression of SSTR2 mRNA. The initial loss of somatostatin was followed by an increase in somatostatin mRNA levels, whereas cortistatin mRNA expression was decreased. In SSTR2-deficient mice with lacZ under the control of the SSTR2 promoter, MCAO-induced upregulation of SSTR2 gene expression was less pronounced than in wild types. SSTR2-deficient mice exhibited a 40% reduction of infarct size after permanent distal MCAO and a 63% reduction after transient proximal MCAO. In summary, we provide direct evidence for activation of SSTR2 by an endogenous ligand after focal ischemia. Activation of functional SSTR2 receptors contributes to increased SSTR2 gene expression and postischemic neurodegeneration.

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

“…Experiments were performed on adult (ages 12-16 weeks; weight 20-30 gm) female mice with a C57BL/6J background. These included wild-type mice (n ϭ 140) and SSTR2-deficient mice (n ϭ 64) (18,19). Animals were housed in a climate-controlled room on a 12-hour light/dark cycle, with water and standard rodent chow available ad libitum.…”

Novel insights in somatostatin receptor physiology

“…Such radioligand accumulation allows tumor imaging by gamma camera scintigraphy (52) and tumor treatment by peptide receptor-targeted radiotherapy (6). Recent studies in transfected host cells expressing sst2 receptor documented that different somatostatin analogs may differentially regulate sst2 receptor signaling and endocytosis (5,37,53). Upon ligand binding, sst2 internalization was triggered by receptor activation.…”

“…Upon ligand binding, sst2 internalization was triggered by receptor activation. Somatostatin antagonists were unable to induce receptor internalization and effectively blocked the agonist-induced internalization (37,53). Actually, somatostatin agonists may differ in their relative potencies for stimulation of the sst2 receptor signaling and endocytosis.…”

Dynamics of Somatostatin Type 2A Receptor Cargoes in Living Hippocampal Neurons

“…Several studies have linked sst2 receptor signaling to the etiology of various CNS disorders including epilepsy (Vezzani and Hoyer, 1999;Csaba et al, 2004Csaba et al, , 2005, ischemia Mastrodimou et al, 2005), and Alzheimer's disease (Saito et al, 2005). The sst 2A receptor rapidly internalizes in the CNS after activation by either endogenous or exogenous ligands (Dournaud et al, 1998;Csaba et al, , 2007Stumm et al, 2004), and therefore represents an interesting receptor model for dynamic studies in living neurons.…”