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Cervia D, Martini D, Ristori C, Catalani E, Timperio AM, Bagnoli P, Casini G: Modulation of the neuronal response to ischaemia by somatostatin analogues in wild-type and knock-out mouse retinas. J Neurochem. 2008 Sep;106(5):2224-35. Epub 2008 Jul 9.
Somatostatin acts at five G protein-coupled receptors, sst (1)-sst (5). In mouse ischaemic retinas, the over-expression of sst (2) (as in sst (1) knock-out mice) results in the reduction of cell death and glutamate release. In this study, we reported that, in wild-type retinas, somatostatin, the multireceptor ligand pasireotide and the sst (2) agonist octreotide decreased ischaemia-induced cell death and that octreotide also decreased glutamate release. In contrast, cell death was increased by blocking sst (2) with cyanamide. In sst (2) over-expressing ischaemic retinas, somatostatin analogues increased cell death, and octreotide also increased glutamate release. To explain this reversal of the anti-ischaemic effect of somatostatin agonists in the presence of sst (2) over-expression, we tested sst (2) desensitisation because of internalisation or altered receptor function. We observed that (i) sst (2) was not internalised, (ii) among G protein-coupled receptor kinases (GRKs) and regulators of G protein signalling (RGSs), GRK1 and RGS1 expression increased following ischaemia, (iii) both GRK1 and RGS1 were down-regulated by octreotide in wild-type ischaemic retinas, (iv) octreotide down-regulated GRK1 but not RGS1 in sst (2) over-expressing ischaemic retinas. These results demonstrate that sst (2) activation protects against retinal ischaemia. However, in the presence of sst (2) over-expression sst (2) is functionally desensitised by agonists, possibly because of sustained RGS1 levels. |
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