Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 370, Issue 2, pp 91–98

Somatostatin coupling to adenylyl cyclase activity in the mouse retina

  • Barbara Pavan
  • Sara Fiorini
  • Massimo Dal Monte
  • Laura Lunghi
  • Carla Biondi
  • Paola Bagnoli
  • Davide Cervia
Original Article


The peptide somatostatin-14 (SRIF) acts in the mammalian retina through its distinct receptors (sst1–5). Scarce information is available on SRIF function in the retina, including the elucidation of transduction pathways mediating SRIF action. We have investigated SRIF and SRIF receptor modulation of adenylyl cyclase (AC) activity in both wild-type (WT) retinas and sst1 or sst2 knock-out (KO) retinas, which are known to over-express sst2 or sst1 receptors respectively. In WT retinas, application of SRIF compounds does not affect forskolin-stimulated AC activity. In contrast, activation of sst1 or sst2 receptors inhibits AC in the presence of sst2 or sst1 receptor antagonists respectively. Results from sst1 KO retinas demonstrate that either SRIF or the sst2 receptor preferring agonist octreotide, pertussis toxin-dependently inhibit AC activity. In contrast, in sst2 KO retinas, neither SRIF nor CH-275, an sst1 receptor agonist, are found to influence AC activity. As revealed by immunoblotting experiments, in sst1 KO retinas, levels of Goα proteins are 60% higher than in WT retinas and this increase in Goα protein levels is concomitant with an increase in sst2A receptor expression. We conclude that interactions between sst1 and sst2 receptors may prevent SRIF effects on AC activity. In addition, we suggest that the density of sst2 receptors and/or Goα proteins may represent the rate-limiting factor for the sst2 receptor-mediated inhibition of AC.


Somatostatin Receptor agonists and antagonists Transduction pathways G proteins Knock-out retina 


  1. Aavik E, Luoto NM, Petrov L, Aavik S, Patel YC, Hayry P (2002) Elimination of vascular fibrointimal hyperplasia by somatostatin receptor 1,4-selective agonist. FASEB J 16:724–726PubMedGoogle Scholar
  2. Bagnoli P, Dal Monte M, Casini G (2003) Expression of neuropeptides and their receptors in the developing retina of mammals. Histol Histopathol 18:1219–1242PubMedGoogle Scholar
  3. Blake AD (2001) Somatostatin receptor subtype 1 (sst(1)) regulates intracellular 3′,5′-cyclic adenosine monophosphate accumulation in rat embryonic cortical neurons: evidence with L-797,591, an sst(1)-subtype-selective nonpeptidyl agonist. Neuropharmacology 40:590–596CrossRefPubMedGoogle Scholar
  4. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  5. Casini G, Dal Monte M, Petrucci C, Gambellini G, Grouselle D, Allen JP, Kreienkamp H-J, Richter D, Epelbaum J, Bagnoli P (2004) Altered morphology of rod bipolar cell axonal terminals in the retinas of mice carrying genetic deletion of somatostatin subtype receptor 1 or 2. Eur J Neurosci 19:43–54PubMedGoogle Scholar
  6. Castanon N, Scearce-Levie K, Lucas JJ, Rocha B, Hen R (2000) Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists. Pharmacol Biochem Behav 67:559–566CrossRefPubMedGoogle Scholar
  7. Cervia D, Fiorini S, Pavan B, Biondi C, Bagnoli P (2002a) Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release. Naunyn-Schmiedebergs Arch Pharmacol 365:200–209CrossRefPubMedGoogle Scholar
  8. Cervia D, Petrucci C, Bluet-Pajot MT, Epelbaum J, Bagnoli P (2002b) Inhibitory control of growth hormone secretion by somatostatin in rat pituitary GC cells: sst(2) but not sst(1) receptors are coupled to inhibition of single-cell intracellular free calcium concentrations. Neuroendocrinology 76:99–110CrossRefPubMedGoogle Scholar
  9. Cervia D, Nunn C, Fehlmann D, Langenegger D, Schuepbach E, Hoyer D (2003a) Pharmacological characterisation of native somatostatin receptors in AtT-20 mouse tumour corticotrophs. Br J Pharmacol 139:109–121CrossRefPubMedGoogle Scholar
  10. Cervia D, Zizzari P, Pavan B, Schuepbach E, Langenegger D, Hoyer D, Biondi C, Epelbaum J, Bagnoli P (2003b) Biological activity of somatostatin receptors in GC rat tumour somatotrophs: evidence with sst1–sst5 receptor-selective nonpeptidyl agonists. Neuropharmacology 44:672–685CrossRefPubMedGoogle Scholar
  11. Colas B, Valencia AM, Prieto JC, Arilla E (1992) Somatostatin binding and modulation of adenylate cyclase in ovine retina membranes. Mol Cell Endocrinol 88:111–117CrossRefPubMedGoogle Scholar
  12. Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132:107–124CrossRefPubMedGoogle Scholar
  13. Cristiani R, Petrucci C, Dal Monte M, Bagnoli P (2002) Somatostatin (SRIF) and SRIF receptors in the mouse retina. Brain Res 936:1–14CrossRefPubMedGoogle Scholar
  14. Dal Monte M, Petrucci C, Cozzi A, Allen JP, Bagnoli P (2003a) Somatostatin inhibits potassium-evoked glutamate release by activation of the sst(2) somatostatin receptor in the mouse retina. Naunyn-Schmiedebergs Arch Pharmacol 367:188–192PubMedGoogle Scholar
  15. Dal Monte M, Petrucci C, Vasilaki A, Cervia D, Grouselle D, Epelbaum J, Kreienkamp HJ, Richter D, Hoyer D, Bagnoli P (2003b) Genetic deletion of somatostatin receptor 1 alters somatostatinergic transmission in the mouse retina. Neuropharmacology 45:1080–1092CrossRefPubMedGoogle Scholar
  16. Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Renal Physiol 279:F400–F416PubMedGoogle Scholar
  17. Firth SI, Boelen MK, Morgan IG (1998) Enkephalin, neurotensin and somatostatin increase cAMP levels in the chicken retina. Aust NZ J Ophthalmol 26 [Suppl 1]:S65–S67Google Scholar
  18. Hoyer D, Dixon K, Gentsch C, Vassout A, Enz A, Jaton A, Nunn C, Schoeffter P, Neumann P, Troxler T, Pfaeffli P (2002) NVP-SRA880, a somatostatin sst1 receptor antagonist promotes social interactions, reduces aggressive behaviour and stimulates learning. Pharmacologist 44:A254Google Scholar
  19. Hummel M, Ansonoff MA, Pintar JE, Unterwald EM (2004) Genetic and pharmacological manipulation of mu opioid receptors in mice reveals a differential effect on behavioral sensitization to cocaine. Neuroscience 125:211–220CrossRefPubMedGoogle Scholar
  20. Insel PA, Ostrom RS (2003) Forskolin as a tool for examining adenylyl cyclase expression, regulation, and G protein signaling. Cell Mol Neurobiol 23:305–314CrossRefPubMedGoogle Scholar
  21. Izquierdo-Claros RM, Boyano-Adanez MC, Torrecillas G, Rodriguez-Puyol M, Arilla-Ferreiro E (2001) Acute modulation of somatostatin receptor function by melatonin in the rat frontoparietal cortex. J Pineal Res 31:46–56CrossRefPubMedGoogle Scholar
  22. Johnson J, Wu V, Wong H, Walsh JH, Brecha NC (1999) Somatostatin receptor subtype 2A expression in the rat retina. Neuroscience 94:675–683CrossRefPubMedGoogle Scholar
  23. Johnson J, Caravelli ML, Brecha NC (2001) Somatostatin inhibits calcium influx into rat rod bipolar cell axonal terminals. Vis Neurosci 18:101–108CrossRefPubMedGoogle Scholar
  24. Kreienkamp HJ, Akgun E, Baumeister H, Meyerhof W, Richter D (1999) Somatostatin receptor subtype 1 modulates basal inhibition of growth hormone release in somatotrophs. FEBS Lett 462:464–466Google Scholar
  25. Mastrodimou N, Thermos K (2004) The somatostatin receptor (sst1) modulates the release of somatostatin in rat retina. Neurosci Lett 356:13–16CrossRefPubMedGoogle Scholar
  26. Moneta D, Richichi C, Aliprandi M, Dournaud P, Dutar P, Billard JM, Carlo AS, Viollet C, Hannon JP, Fehlmann D, Nunn C, Hoyer D, Epelbaum J, Vezzani A (2002) Somatostatin receptor subtypes 2 and 4 affect seizure susceptibility and hippocampal excitatory neurotransmission in mice. Eur J Neurosci 16:843–849CrossRefPubMedGoogle Scholar
  27. Nunn C, Schoeffter P, Langenegger D, Hoyer D (2003) Functional characterisation of the putative somatostatin sst2 receptor antagonist CYN 154806. Naunyn-Schmiedebergs Arch Pharmacol 367:1–9PubMedGoogle Scholar
  28. Ostrom RS, Post SR, Insel PA (2000) Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving G(s). J Pharmacol Exp Ther 294:407–412PubMedGoogle Scholar
  29. Petrucci C, Resta V, Fieni F, Bigiani A, Bagnoli P (2001) Modulation of potassium current and calcium influx by somatostatin in rod bipolar cells isolated from the rabbit retina via sst2 receptors. Naunyn-Schmiedebergs Arch Pharmacol 363:680–694CrossRefPubMedGoogle Scholar
  30. Pfeiffer M, Koch T, Schroder H, Klutzny M, Kirscht S, Kreienkamp HJ, Hollt V, Schulz S (2001) Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J Biol Chem 276:14027–14036CrossRefPubMedGoogle Scholar
  31. Pollock DM (2001) Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1. Physiol Genomics 6:39–43PubMedGoogle Scholar
  32. Rocheville M, Lange DC, Kumar U, Sasi R, Patel RC, Patel YC (2000) Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem 275:7862–7869CrossRefPubMedGoogle Scholar
  33. Schorderet M, Sovilla JY, Magistretti PJ (1981) VIP- and glucagon-induced formation of cyclic AMP in intact retinae in vitro. Eur J Pharmacol 71:131–133CrossRefPubMedGoogle Scholar
  34. Schulz S, Schreff M, Schmidt H, Handel M, Przewlocki R, Hollt V (1998) Immunocytochemical localization of somatostatin receptor sst2A in the rat spinal cord and dorsal root ganglia. Eur J Neurosci 10:3700–3708CrossRefPubMedGoogle Scholar
  35. Thermos K (2003) Functional mapping of somatostatin receptors in the retina: a review. Vision Res 43:1805–1815CrossRefPubMedGoogle Scholar
  36. Vasilaki A, Gardette R, Epelbaum J, Thermos K (2001) NADPH-diaphorase colocalization with somatostatin receptor subtypes sst2A and sst2B in the retina. Invest Ophthalmol Vis Sci 42:1600–1609PubMedGoogle Scholar
  37. Vasilaki A, Mouratidou M, Schulz S, Thermos K (2002) Somatostatin mediates nitric oxide production by activating sst(2) receptors in the rat retina. Neuropharmacology 43:899–909CrossRefPubMedGoogle Scholar
  38. Vasilaki A, Georgoussi Z, Thermos K (2003) Somatostatin receptors (sst2) are coupled to Go and modulate GTPase activity in the rabbit retina. J Neurochem 84:625–632CrossRefPubMedGoogle Scholar
  39. Watling KJ, Dowling JE (1983) Effects of vasoactive intestinal peptide and other peptides on cyclic AMP accumulation in intact pieces and isolated horizontal cells of the teleost retina. J Neurochem 41:1205–1213PubMedGoogle Scholar
  40. Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2:999–1017CrossRefPubMedGoogle Scholar
  41. Zalutsky RA, Miller RF (1990) The physiology of somatostatin in the rabbit retina. J Neurosci 10:383–393PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Barbara Pavan
    • 1
  • Sara Fiorini
    • 1
  • Massimo Dal Monte
    • 2
  • Laura Lunghi
    • 1
  • Carla Biondi
    • 1
  • Paola Bagnoli
    • 2
  • Davide Cervia
    • 2
  1. 1.Dipartimento di Biologia, Sez. di Fisiologia GeneraleUniversità di FerraraFerraraItaly
  2. 2.Dipartimento di Fisiologia e Biochimica “G. Moruzzi”Università di PisaPisaItaly

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