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, 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.