Skip to main content

Coexpression of Multiple Somatostatin Receptors in Individual Cells

  • Chapter
Somatostatin

Part of the book series: Endocrine Updates ((ENDO,volume 24))

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abdalla, S., Zaki, E., Lother, H., Quitterer, U. Involvement of the amino terminus of the B(2) receptor in agonist-induced receptor dimerization. J Biol Chem 1999, 274:26079–26084.

    Article  CAS  PubMed  Google Scholar 

  2. Akopian, A., Johnson, J., Gabriel, R., Brecha, N., Witkovsky, P. Somatostatin modulates voltage-gated K(+) and Ca(2+) currents in rod and cone photoreceptors of the salamander retina. J Neurosci 2000, 20:929–936.

    CAS  PubMed  Google Scholar 

  3. Bruno, J.F., Xu, Y., Berelowitz, M. Somatostatin regulates somatostatin receptor subtype mRNA expression in GH3 cells. Biochem Biophys Res Commun 1994, 202:1738–1743.

    Article  CAS  PubMed  Google Scholar 

  4. Bruno, J.F., Xu, Y., Song, J., Berelowitz, M. Molecular cloning and functional expression of a brain-specific somatostatin receptor. Proc Natl Acad Sci USA 1992, 89:11151–11155.

    CAS  PubMed  Google Scholar 

  5. Bruno, J.F., Xu, Y., Song, J., Berelowitz, M. Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 1993, 133:2561–2567.

    CAS  PubMed  Google Scholar 

  6. Buscail, L., Delesque, N., Esteve, J.P., Saint-Laurent, N., Prats, H., Clerc, P., Robberecht, P., Bell, G.I., Liebow, C., Schally, A.V., et al. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci USA 1994, 91:2315–2319.

    CAS  PubMed  Google Scholar 

  7. Charles, A.C., Mostovskaya, N., Asas, K., Evans, C.J., Dankovich, M.L., Hales, T.G. Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory. Mol Pharmacol. 2003, 63:89–95.

    Article  CAS  PubMed  Google Scholar 

  8. Cristiani, R., Fontanesi, G., Casini, G., Petrucci, C., Viollet, C., Bagnoli, P. Expression of somatostatin subtype 1 receptor in the rabbit retina. Invest Ophthalmol Vis Sci 2000, 41:3191–3199.

    CAS  PubMed  Google Scholar 

  9. Csaba Z., Dournaud, P. Cellular biology of somatostatin receptors. Neuropeptides 2001, 35:1–23.

    Article  CAS  PubMed  Google Scholar 

  10. Day, R., Dong, W., Panetta, R., Kraicer, J., Greenwood, M.T., Patel, Y.C. Expression of mRNA for somatostatin receptor (sstr) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis. Endocrinology 1995, 136:5232–5235.

    Article  CAS  PubMed  Google Scholar 

  11. Delfs, J.R., Dichter, M.A. Effects of somatostatin on mammalian cortical neurons in culture: physiological actions and unusual dose response characteristics. J Neurosci 1983, 3:1176–1188.

    CAS  PubMed  Google Scholar 

  12. Devi, L.A. G-protein-coupled receptor dimers in the lime light. Trends Pharmacol Sci 2000, 21:324–326.

    Article  CAS  PubMed  Google Scholar 

  13. Dournaud, P., Boudin, H., Schonbrunn, A., Tannenbaum, G.S., Beaudet, A. Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin. J Neurosci 1998, 18:1056–1071.

    CAS  PubMed  Google Scholar 

  14. Dournaud, P., Gu, Y.Z., Schonbrunn, A., Mazella, J., Tannenbaum, G.S., Beaudet, A. Localization of the somatostatin receptor SST2A in rat brain using a specific anti-peptide antibody. J Neurosci 1996, 16:4468–4478.

    CAS  PubMed  Google Scholar 

  15. Dournaud, P., Slama, A., Beaudet, A., and Epelbaum, J. “Somatostatin receptors.” In Handbook of Chemical Neuroanatomy, Vol. 16:Peptide receptors Part I, R. Quirion, A. Björklund, T. Hökfelt, eds. Amsterdam: Elsevier, 1999.

    Google Scholar 

  16. Epelbaum, J., Dournaud, P., Fodor, M., and Viollet, C. The neurobiology of somatostatin. Crit Rev Neurobiol 1994, 8:25–44.

    CAS  PubMed  Google Scholar 

  17. Florio, T., Yao, H., Carey, K.D., Dillon, T.J., and Stork, P.J. Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). Mol Endocrinol 1999, 13:24–37.

    Article  CAS  PubMed  Google Scholar 

  18. Fontanesi, G., Gargini, C., and Bagnoli, P. Postnatal development of somatostatin 2A (sst2A) receptors expression in the rabbit retina. Dev Brain Res 2000, 123:67–80.

    Article  CAS  Google Scholar 

  19. Gardette, R., Faivre-Bauman, A., Loudes, C., Kordon, C., Epelbaum, J. Modulation by somatostatin of glutamate sensitivity during development of mouse hypothalamic neurons in vitro. Dev Brain Res 1995, 86:123–133.

    Article  CAS  Google Scholar 

  20. George, S.R., Lee, S.P., Varghese, G., Zeman, P.R., Seeman, P., Ng, G.Y., and O’Down, B.F. A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization. J Biol Chem 1998, 273:30244–30248.

    CAS  PubMed  Google Scholar 

  21. Händel, M., Schulz, S., Stanarius, A., Schreff, M., Erdtmann-Vourliotis, M., Schmidt, H., Wolf, G., Höllt, V. Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience 1999, 89:909–926.

    Article  PubMed  Google Scholar 

  22. Hebert, T.E., Moffett, S., Morello, J.P., Loisel, T.P., Bichet, D.G., Barret, C., Bouvier, M. A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem 1996, 271:16384–16392.

    Article  CAS  PubMed  Google Scholar 

  23. Helboe, L., Moller, M. Immunohistochemical localization of somatostatin receptor subtypes sst1 and sst2 in the rat retina. Invest Ophthalmol Vis Sci 1999, 40:2376–2382.

    CAS  PubMed  Google Scholar 

  24. Helboe, L., Stidsen, C.E., Moller, M. Immunohistochemical and cytochemical localization of the somatostatin receptor subtype sst1 in the somatostatinergic parvocellular neuronal system of the rat hypothalamus. J Neurosci 1998, 18:4938–4945.

    CAS  PubMed  Google Scholar 

  25. Hervieu, G., Emson, P.C. The localization of somatostatin receptor 1 (sst1) immunoreactivity in the rat brain using an N-terminal specific antibody. Neuroscience 1998, 85:1263–1284.

    Article  CAS  PubMed  Google Scholar 

  26. Hou, C., Gilbert, R.L., Barber, D.L. Subtype-specific signaling mechanisms of somatostatin receptors SSTR1 and SSTR2. J Biol Chem 1994, 269:10357–10362.

    CAS  PubMed  Google Scholar 

  27. Johnson, J., Wu, V., Wong, H., Walsh, J.H., Brecha, N.C. Somatostatin receptor subtype 2A expression in the rat retina. Neuroscience 1999, 94:675–683.

    Article  CAS  PubMed  Google Scholar 

  28. Krantic, S., Quirion, R., Uhl, G. “Somatostatin receptors.” In Handbook of Chemical Neuroanatomy, Vol. 11:Neuropeptide receptors in the CNS, A. Björklund, T. Hökfelt, M.J. Kuhar, eds. Amsterdam: Elsevier, 1992.

    Google Scholar 

  29. Krempels, K., Hunyady, B., O’Carroll, A.M., Mezey, E. Distribution of somatostatin receptor messenger RNAs in the rat gastrointestinal tract. Gastroenterology 1997, 112:1948–1960.

    Article  CAS  PubMed  Google Scholar 

  30. Kumar, U., Laird, D., Srikant, C.B., Escher, E., Patel, Y.C. Expression of the five somatostatin receptor (SSTR1-5) subtypes in rat pituitary somatotrophs: quantitative analysis by double-layer immunofluorescence confocal microscopy. Endocrinology 1997, 138:4473–4476.

    Article  CAS  PubMed  Google Scholar 

  31. Kumar, U., Ong, W., Patel, S., Patel, Y.C. Cellular expression of the five somatostatin receptor subtypes (sstr1-5) in rat hypothalamus: a comparative immunohistochemical analysis. Proceedings of The Endocrine Society’s 81st Annual Meeting, 1999 June 12–15; San Diego, 1999a.

    Google Scholar 

  32. Kumar, U., Sasi, R., Suresh, S., Patel, A., Thangaraju, M., Metrakos, P., Patel, S.C., Patel, Y.C. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes 1999b, 48:77–85.

    CAS  PubMed  Google Scholar 

  33. Lanneau, C., Bluet-Pajot, M. T., Zizzari, P., Csaba, Z., Dournaud, P., Helboe, L., Hoyer, D., Pellegrini, E., Tannenbaum, G. S., Epelbaum, J., Gardette, R. Involvement of the Sst1 somatostatin receptor subtype in the intrahypothalamic neuronal network regulating growth hormone secretion: an in vitro and in vivo antisense study. Endocrinology 2000a, 141:967–979.

    Article  CAS  PubMed  Google Scholar 

  34. Lanneau, C., Peineau, S., Petit, F., Epelbaum, J., Gardette, R. Somatostatin modulation of excitatory synaptic transmission between periventricular and arcuate hypothalamic nuclei in vitro. J Neurophysiol 2000b, 84: 1464–1474.

    CAS  PubMed  Google Scholar 

  35. Lanneau, C., Viollet, C., Faivre-Bauman, A., Loudes, C., Kordon, C., Epelbaum, J., Gardette, R. Somatostatin receptor subtypes sst1 and sst2 elicit opposite effects on the response to glutamate of mouse hypothalamic neurones: an electrophysiological and single cell RT-PCR study. Eur J Neurosci 1998, 10:204–212.

    Article  CAS  PubMed  Google Scholar 

  36. Lim, S., Naisbitt, S., Yoon, J., Hwang, J.I., Suh, P.G., Sheng, M., Kim, E. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J Biol Chem 1999, 274:29510–29518.

    CAS  PubMed  Google Scholar 

  37. Meyerhof, W., Wulfsen, I., Schonrock, C., Fehr, S., Richter, D. Molecular cloning of a somatostatin-28 receptor and comparison of its expression pattern with that of a Mezey, E., Hunyady, B., Mitra, S., Hayes, E., Liu, Q., Schaeffer, J., Schonbrunn, A. Cell specific expression of the sst2A and sst5 somatostatin receptors in the rat anterior pituitary. Endocrinology 1998, 139:414–419.

    Google Scholar 

  38. Naisbitt, S., Kim, E., Tu, J.C., Xiao, B., Sala, C., Valtschanoff, J., Weinberg, R.J., Worley, P.F., Sheng, M. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 1999, 23:569–582.

    Article  CAS  PubMed  Google Scholar 

  39. Nilsson, L., Folkesson, R. Coexistence of somatostatin receptor subtypes in the human neuroblastoma cell line LA-N-2. FEBS Lett 1997, 401:83–88.

    Article  CAS  PubMed  Google Scholar 

  40. O’Carroll, A.M., Krempels, K. Widespread distribution of somatostatin receptor messenger ribonucleic acids in rat pituitary. Endocrinology 1995, 136:5224–5227.

    CAS  PubMed  Google Scholar 

  41. O’Carroll, A.M., Lolait, S.J., Konig, M., Mahan, L.C. Molecular cloning and expression of a pituitary somatostatin receptor with preferential affinity for somatostatin-28. Mol Pharmacol 1992, 42, 939–946.

    CAS  PubMed  Google Scholar 

  42. Overton, M.C., Blumer, K.J. G-protein-coupled receptors function as oligomers in vivo. Curr Biol 2000, 10:341–344.

    Article  CAS  PubMed  Google Scholar 

  43. Patel, Y.C. Somatostatin and its receptor family. Front Neuroendocrinol 1999, 20:157–198.

    CAS  PubMed  Google Scholar 

  44. Patel, Y.C., Panetta, R., Escher, E., Greenwood, M., Srikant, C.B. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype. J Biol Chem 1994, 269:1506–1509.

    CAS  PubMed  Google Scholar 

  45. Perez, J., Hoyer, D. Co-expression of somatostatin SSTR-3 and SSTR-4 receptor messenger RNAs in the rat brain. Neuroscience 1995, 64:241–253.

    Article  CAS  PubMed  Google Scholar 

  46. Pfeiffer, M., Koch, T., Schroder, H., Klutzny, M., Kirscht, S., Kreienkamp, HJ., Höllt, V., Schulz, S. Homo-and heterodimerization of somatostatin receptor subtypes. Inactivation of sst3 receptor function by heterodimerization with sst2A. J Biol Chem 2001, 276:14027–14036.

    Article  CAS  PubMed  Google Scholar 

  47. Pfeiffer, M., Koch, T., Schroder, H., Laugsch, M., Hollt, V., Schulz, S. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem 2002, 277:19762–19772.

    Article  CAS  PubMed  Google Scholar 

  48. Reardon, D.B., Dent, P., Wood, S.L., Kong, T., Sturgill, T.W. Activation in vitro of somatostatin receptor subtypes 2, 3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected Ras-transformed NIH 3T3 cells: coexpression with catalytically inactive SHP-2 blocks responsiveness. Mol Endocrinol 1997, 11:1062–1069.

    Article  CAS  PubMed  Google Scholar 

  49. Rocheville, M., Lange, D.C., Kumar, U., Patel, S.C., Patel, R.C., Patel, Y.C. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000a, 288:154–157.

    Article  CAS  PubMed  Google Scholar 

  50. Rocheville, M., Lange, D.C., Kumar, U., Sasi, R., Patel, R.C., Patel, Y.C. Subtypes of the somatostatin receptor assemble as functional homo-and heterodimers. J Biol Chem 2000b, 275:7862–7869.

    Article  CAS  PubMed  Google Scholar 

  51. Schindler, M., Harrington, K.A., Humphrey, P.P., Emson, P.C. Cellular localization and co-expression of somatostatin receptor messenger RNAs in the human brain. Mol Brain Res 1995, 34:321–326.

    Article  CAS  PubMed  Google Scholar 

  52. Schindler, M., Holloway, S., Hathway, G., Woolf, C.J., Humphrey, P.P., Emson, P.C. Identification of somatostatin sst2(a) receptor expressing neurones in central regions involved in nociception. Brain Res 1998, 798:25–35.

    Article  CAS  PubMed  Google Scholar 

  53. Schindler, M., Humphrey, P. P., Emson, P. C. Somatostatin receptors in the central nervous system. Prog Neurobiol 1996, 50:9–47.

    Article  CAS  PubMed  Google Scholar 

  54. Schindler, M., Humphrey, P.P., Lohrke, S., Friauf, E. Immunohistochemical localization of the somatostatin sst2(b) receptor splice variant in the rat central nervous system. Neuroscience 1999, 90:859–874.

    Article  CAS  PubMed  Google Scholar 

  55. Schindler, M., Sellers, L.A., Humphrey, P.P., Emson, P.C. Immunohistochemical localization of the somatostatin SST2(A) receptor in the rat brain and spinal cord. Neuroscience 1997, 76:225–240.

    CAS  PubMed  Google Scholar 

  56. Schreff, M., Schulz, S., Händel, M., Keilhoff, G., Braun, H., Pereira, G., Klutzny, M., Schmidt, H., Wolf, G., Höllt, V. Distribution, targeting, and intemalization of the sst4 somatostatin receptor in rat brain. J Neurosci 2000, 20:3785–3797.

    CAS  PubMed  Google Scholar 

  57. Schulz, S., Händel, M., Schreff, M., Schmidt, H., Höllt, V. Localization of five somatostatin receptors in the rat central nervous system using subtype-specific antibodies. J Physiol Paris 2000, 94:259–264.

    CAS  PubMed  Google Scholar 

  58. Schulz, S., Schmidt, H., Händel, M., Schreff, M., Höllt, V. Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord. Neurosci Lett 1998, 257:37–40.

    Article  CAS  PubMed  Google Scholar 

  59. Schwarzler, A., Kreienkamp, HJ., Richter, D. Interaction of the somatostatin receptor subtype 1 with the human homolog of the Shk1 kinase-binding protein from yeast. J Biol Chem 2000, 275:9557–9562.

    Article  CAS  PubMed  Google Scholar 

  60. Segond von Banchet, G., Schindler, M., Hervieu, G.J., Beckmann, B., Emson, P.C., Heppelmann, B. Distribution of somatostatin receptor subtypes in rat lumbar spinal cord examined with gold-labelled somatostatin and anti-receptor antibodies. Brain Res 1999, 816:254–257.

    Google Scholar 

  61. Seimer, I., Schindler, M., Allen, J.P., Humphrey, P.P., Emson, P.C. Advances in understanding neuronal somatostatin receptors. Regul Peptides 2000a, 90:1–18.

    Google Scholar 

  62. Seimer, I.S., Schindler, M., Humphrey, P.P., Emson, P.C. Immunohistochemical localization of the somatostatin sst(4) receptor in rat brain. Neuroscience 2000b, 98:523–533.

    Google Scholar 

  63. Stroh, T., Kreienkamp, H.J., Beaudet, A. Immunohistochemical distribution of the somatostatin receptor subtype 5 in the adull rat brain: predominant expression in the basal forebrain. J Comp Neurol 1999, 412:69–82.

    Article  CAS  PubMed  Google Scholar 

  64. Tannenbaum, G.S., Zhang, W.H., Lapointe, M., Zeitler, P., Beaudet, A. Growth hormone-releasing hormone neurons in the arcuate nucleus express both Sst1 and Sst2 somatostatin receptor genes. Endocrinology 1998, 139:1450–1453.

    CAS  PubMed  Google Scholar 

  65. Traina, G., Lanneau, C., Amoux, A., Porokhov, B., Bagnoli, P., Epelbaum, J. Expression and coupling of somatostatin receptors in rat adrenal (PC12) and pituitary (GC) cell lines. Neurosci Lett 1998, 252:131–134.

    Article  CAS  PubMed  Google Scholar 

  66. Tu, J.C., Xiao, B., Naisbitt, S., Yuan, J.P., Petralia, R.S., Brakeman, P., Doan, A., Aakalu, V.K., Lanahan, A.A., Sheng, M., Worley, P.F. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 1999, 23:583–592.

    Article  CAS  PubMed  Google Scholar 

  67. Vasilaki, A., Gardette, R., Epelbaum, J., Thermos, K. NADPH-diaphorase colocalizes with somatostatin receptor subtypes sst2A and sst2B in the retina. Invest Ophthalmol Vis Sci, in press.

    Google Scholar 

  68. Viollet, C., Lanneau, C., Faivre-Bauman, A., Zhang, J., Djordjijevic, D., Loudes, C., Gardette, R., Kordon, C., Epelbaum, J. Distinct patterns of expression and physiological effects of sst1 and sst2 receptor subtypes in mouse hypothalamic neurons and astrocytes in culture. J Neurochem 1997, 68:2273–2280.

    CAS  PubMed  Google Scholar 

  69. Xu, Y., Berelowitz, M., Bruno, J.F. Dexamethasone regulates somatostatin receptor subtype messenger ribonucleic acid expression in rat pituitary GH4C1 cells. Endocrinology 1995, 136:5070–5075.

    CAS  PubMed  Google Scholar 

  70. Yao, I., Hata, Y., Hirao, K., Deguchi, M., Ide, N., Takeuchi, M., Takai, Y. Synamon, a novel neuronal protein interacting with synapse-associated protein 90/postsynaptic density-95-associated protein. J Biol Chem 1999, 274:27463–27466.

    CAS  PubMed  Google Scholar 

  71. Yamada, Y., Post, S.R., Wang, K., Tager, H.S., Bell, G.I., Seino, S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci USA 1992a, 89:251–255.

    CAS  PubMed  Google Scholar 

  72. Yamada, Y., Reisine, T., Law, S.F., Ihara, Y., Kubota, A., Kagimoto, S., Seino, M., Seino, Y., Bell, G.I., Seino, S. Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. Mol Endocrinol 1992b, 6:2136–2142.

    Article  CAS  PubMed  Google Scholar 

  73. Zhu, L.J., Krempels, K., Bardin, C.W., O’Carroll, A.M., Mezey, E. The localization of messenger ribonucleic acids for somatostatin receptors 1, 2, and 3 in rat testis. Endocrinology 1998, 139:350–357

    CAS  PubMed  Google Scholar 

  74. Zitzer, H., Honck, H.H., Bachner, D., Richter, D., Kreienkamp, HJ. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain. J Biol Chem 1999a, 274:32997–33001.

    CAS  PubMed  Google Scholar 

  75. Zitzer, H., Richter, D., Kreienkamp, HJ. Agonist-dependent interaction of the rat somatostatin receptor subtype 2 with cortactin-binding protein 1. J Biol Chem 1999b, 274:18153–18156.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science + Business Media, Inc.

About this chapter

Cite this chapter

Gardette, R., Petit, F., Peineau, S., Lanneau, C., Epelbaum, J. (2004). Coexpression of Multiple Somatostatin Receptors in Individual Cells. In: Srikant, C.B. (eds) Somatostatin. Endocrine Updates, vol 24. Springer, Boston, MA. https://doi.org/10.1007/1-4020-8033-6_8

Download citation

  • DOI: https://doi.org/10.1007/1-4020-8033-6_8

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4020-7799-9

  • Online ISBN: 978-1-4020-8033-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics