Modulation of the neuronal response to ischaemia by somatostatin analogues in wild-type and knock-out mouse retinas

Somatostatin acts at five G protein-coupled receptors, sst₁-sst₅. In mouse ischaemic retinas, the over-expression of sst₂ (as in sst₁ 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 sst₂ agonist octreotide decreased ischaemia-induced cell death and that octreotide also decreased glutamate release. In contrast, cell death was increased by blocking sst₂ with cyanamide. In sst₂ 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 sst₂ over-expression, we tested sst₂ desensitisation because of internalisation or altered receptor function. We observed that (i) sst₂ 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 sst₂ over-expressing ischaemic retinas. These results demonstrate that sst₂ activation protects against retinal ischaemia. However, in the presence of sst₂ over-expression sst₂ is functionally desensitised by agonists, possibly because of sustained RGS1 levels.