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.
Cervia
Davide
D
Department of Environmental Sciences, University of Tuscia, Largo dell'Università snc, Viterbo. d.cervia@unitus.it
Martini
Davide
D
Ristori
Chiara
C
Catalani
Elisabetta
E
Timperio
Anna Maria
AM
Bagnoli
Paola
P
Casini
Giovanni
G
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003484:Cyanamide / Q000494:pharmacology; D005260:Female; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D020710:RGS Proteins / Q000187:drug effects / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism
D009842:Oligopeptides; D020710:RGS Proteins; D017481:Receptors, Somatostatin; C488188:Rgs1 protein, mouse; C492049:Sstr2 protein, mouse; D003484:Cyanamide; D013004:Somatostatin; C517782:pasireotide; D051606:G-Protein-Coupled Receptor Kinase 1; C496762:Grk1 protein, mouse; D015282:Octreotide