, Volume 184, Issue 1, pp 82–86 | Cite as

The N251K functional polymorphism in the α2A-adrenoceptor gene is not associated with depression: a study in suicide completers

  • Idoia Martín-Guerrero
  • Luis F. Callado
  • Koldo Saitua
  • Guadalupe Rivero
  • África García-Orad
  • J. Javier MeanaEmail author
Original Investigation



α2A-Adrenoceptor up-regulation and supersensitivity have been described in the postmortem brains of depressed suicide victims and in the platelets of depressed subjects. The C to G transversion at nucleotide 753 (Asn to Lys change at amino acid 251 or N251K) is a low-frequency polymorphism of the α2A-adrenoceptor gene that results in a gain-of-function phenotype. A previous study has suggested an association between completed suicide and this polymorphism.


The single functional polymorphism N251K was tested in a large sample (n=214) of completed suicides, controlling for the antemortem psychiatric diagnosis, and matched controls (n=176).


Postmortem brain DNA was extracted and the α2A-adrenoceptor gene fragment was amplified by polymerase chain reaction, followed by a StyI restriction endonuclease digestion. Amplified products were sequenced to confirm the presence of the α2A-adrenoceptor gene fragment where the polymorphism is located.


The N251K polymorphism was absent in both suicide victim and control groups. No association between the polymorphism and suicide or depression was established.


The N251K polymorphism does not represent a genetic factor to explain the α2A-adrenoceptor hyperactivity in the brains of depressed suicide victims. Association between suicide and this polymorphism was not replicated.


Alpha-2 adrenergic receptors Suicide Single nucleotide polymorphism Depression Genetics Human brain Haplotype 



This study was supported by grants from the Spanish Ministerio de Sanidad y Consumo [Fondo de Investigación Sanitaria 04/0190 and Redes Temáticas de Investigación Cooperativa Sanitaria (RETICS) G03/179] and Ministerio de Ciencia y Tecnologia (SAF 02/10370E), the Basque Government (ETORTEK and SAIOTEK), the University of the Basque Country (13588/01), and cofinanced by European Regional Development Funds.

The authors wish to thank the staff members of the Basque Institute of Legal Medicine for their cooperation in the study. IM-G and GR are recipients of predoctoral fellowships from RETICS and the Basque Government, respectively.


  1. Bolonna AA, Arranz MJ, Munro J, Osborne S, Petouni M, Martinez M, Kerwin RW (2000) No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 280:65–68PubMedCrossRefGoogle Scholar
  2. Callado LF, Meana JJ, Grijalba B, Pazos A, Sastre M, García-Sevilla JA (1998) Selective increase of α2A-adrenoceptor agonist binding sites in brains of depressed suicide victims. J Neurochem 70:1114–1123PubMedCrossRefGoogle Scholar
  3. De Paermentier F, Mauger JM, Lowther S, Crompton MR, Katona CLE, Horton RW (1997) Brain α-adrenoceptors in depressed suicides. Brain Res 757:60–68PubMedCrossRefGoogle Scholar
  4. Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD (2002) High-activity-related allele of MAO—A gene associated with depressed suicide in males. Neuroreport 13:1195–1198PubMedCrossRefGoogle Scholar
  5. Fernández-Pastor B, Mateo Y, Gómez-Urquijo S, Meana JJ (2005) Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis. Psychopharmacology 180:570–579PubMedCrossRefGoogle Scholar
  6. Feuerstein TJ, Mutschler A, Lupp A, Van Velthoven V, Schlicker E, Göthert M (1993) Endogenous noradrenaline activates α2-adrenoceptors on serotonergic nerve endings in human and rat neocortex. J Neurochem 61:474–480PubMedCrossRefGoogle Scholar
  7. García-Sevilla JA (1989) The platelet α2-adrenoceptor as a potential biological marker in depression. Br J Psychiatry 154(suppl 4):67–72PubMedGoogle Scholar
  8. García-Sevilla JA, Escribá PV, Ozaita A, La Harpe R, Walzer C, Eytan A, Guimón J (1999) Up-regulation of immunolabeled α2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 72:282–291PubMedCrossRefGoogle Scholar
  9. García-Sevilla JA, Ventayol P, Pérez V, Rubovszky G, Puigdemont D, Ferrer-Alcón M et al (2004) Regulation of platelet α2A-adrenoceptors, Gi proteins and receptor kinases in major depression: effects of mirtazapine treatment. Neuropsychopharmacology 29:580–588PubMedCrossRefGoogle Scholar
  10. González AM, Pascual J, Meana JJ, Barturen F, del Arco C, Pazos A, García-Sevilla JA (1994) Autoradiographic demonstration of increased α2-adrenoceptor agonist binding sites in the hippocampus and frontal cortex of depressed suicide victims. J Neurochem 63:256–265PubMedGoogle Scholar
  11. González-Maeso J, Rodríguez-Puertas R, Meana JJ, García-Sevilla JA, Guimón J (2002) Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors. Mol Psychiatry 7:755–767PubMedCrossRefGoogle Scholar
  12. Gross-Isseroff R, Weizman A, Fieldust SJ, Israeli M, Biegon A (2000) Unaltered α2-noradrenergic/imidazoline receptors in suicide victims: a postmortem brain autoradiographic analysis. Eur Neuropsychopharmacol 10:265–271PubMedCrossRefGoogle Scholar
  13. Invernizzi RW, Parini S, Sacchetti G, Fracasso C, Caccia S, Annoni K, Samanin R (2001) Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize α2-adrenoceptors in the prefrontal cortex. Br J Pharmacol 132:183–188PubMedCrossRefGoogle Scholar
  14. Isometsä ET (2000) Suicide. Curr Opin Psychiatry 13:143–147CrossRefGoogle Scholar
  15. Klimek V, Rajkowska G, Luker SN, Dilley G, Meltzer HY, Overholser JC, Stockmeier CA, Ordway GA (1999) Brain noradrenergic receptors in major depression and schizophrenia. Neuropsychopharmacology 21:69–81PubMedCrossRefGoogle Scholar
  16. Lin P-Y, Tsai G (2004) Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry 55:1023–1030PubMedCrossRefGoogle Scholar
  17. Maris RW (2002) Suicide. Lancet 360:319–326PubMedCrossRefGoogle Scholar
  18. Mateo Y, Pineda J, Meana JJ (1998) Somatodendritic α2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation or cortical noradrenaline release by the antidepressant desipramine. J Neurochem 71:790–798PubMedGoogle Scholar
  19. Mateo Y, Fernández-Pastor, B, Meana JJ (2001) Acute and chronic effects of desipramine and clorgyline on α2-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual probe microdialysis study. Br J Pharmacol 133:1362–1370PubMedCrossRefGoogle Scholar
  20. Meana JJ, García-Sevilla JA (1987) Increased α2-adrenoceptor density in the frontal cortex of depressed suicide victims. J Neural Transm 70:377–381PubMedCrossRefGoogle Scholar
  21. Meana JJ, Barturen F, García-Sevilla JA (1992) α2-Adrenoceptors in the brain of suicide victims: increased receptor density associated with major depression. Biol Psychiatry 31:471–490PubMedCrossRefGoogle Scholar
  22. Mongeau R, De Montigny C, Blier P (1994) Electrophysiologic evidence for desensitization of α2-adrenoceptors on serotonergic terminals following long-term treatment with drugs increasing norepinephrine synaptic concentration. Neuropsychopharmacology 10:41–51PubMedGoogle Scholar
  23. Ohara K, Nagai M, Tani K, Tsukamoto T, Suzuki Y, Ohara K (1998) Polymorphism in the promoter region of the α2A-adrenergic receptor gene and mood disorders. Neuroreport 9:1291–1294PubMedGoogle Scholar
  24. Ohara K, Suzuki Y, Ochiai M, Terada H, Ohara K (2000) Polymorphism in the promoter region of the alpha2A-adrenergic receptor gene and panic disorders. Psychiatry Res 93:79–82PubMedCrossRefGoogle Scholar
  25. Ono H, Shirakawa O, Nushida H, Ueno Y, Maeda K (2004) Association between catechol-O-methyltransferase functional polymorphism and male suicide completers. Neuropsychopharmacology 29:1374–1377PubMedCrossRefGoogle Scholar
  26. Ordway GA, Schenk J, Stockmeier CA, May W, Klimek V (2003) Elevated agonist binding to α2-adrenoceptors in the locus coeruleus in major depression. Biol Psychiatry 53:315–323PubMedCrossRefGoogle Scholar
  27. Piletz JE, Schubert DSP, Halaris A (1986) Evaluation of studies of platelet α2-adrenoceptors in depressive illness. Life Sci 39:1589–1616PubMedCrossRefGoogle Scholar
  28. Raiteri M, Bonanno G, Maura G, Pende M, Andrioli GC, Ruelle A (1992) Subclassification of release-regulating α2-autoreceptors in human brain cortex. Br J Pharmacol 107:1146–1151PubMedGoogle Scholar
  29. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, PlainviewGoogle Scholar
  30. Sequeira A, Mamdani F, Lalovic A, Anguelova M, Lesage A, Seguin M, Chawky N, Desautels A, Turecki G (2004) Alpha 2A adrenergic receptor gene and suicide. Psychiatry Res 125:87–93PubMedCrossRefGoogle Scholar
  31. Sibille E, Arango V, Galfalvy HC, Pavlidis P, Erraji-Benchekroun L, Ellis SP, Mann JJ (2004) Gene expression profiling of depression and suicide in human prefrontal cortex. Neuropsychopharmacology 29:351–361PubMedCrossRefGoogle Scholar
  32. Small KM, Forbes SL, Brown KM, Liggett SB (2000) An Asn to Lys polymorphism in the third intracellular loop of the human α2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling. J Biol Chem 275:38518–38523PubMedCrossRefGoogle Scholar
  33. Small KM, Liggett SB (2001) Identification and functional characterization of α2-adrenoceptor polymorphisms. Trends Pharmacol Sci 22:471–477PubMedCrossRefGoogle Scholar
  34. Small KM, McGraw DW, Liggett SB (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 43:381–411PubMedCrossRefGoogle Scholar
  35. Tsai S-J, Wang Y-C, Younger W-YY, Lin C-H, Yang KH, Hong C-J (2001) Association analysis of polymorphism in the promoter region of the α2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res 49:53–58PubMedCrossRefGoogle Scholar
  36. Turecki G, Zhu Z, Tzenova J, Lesage A, Séguin M, Tousignant M, Chawky N, Vanier C, Lipp O, Alda M, Joober R, Benkelfat C, Rouleau GA (2001) TPH and suicidal behavior: a study in suicide completers. Mol Psychiatry 6:98–102PubMedCrossRefGoogle Scholar
  37. Turecki G, Sequeira A, Gingras Y, Seguin M, Lesage A, Tousignant M, Chawky N, Vanier C, Lipp O, Benkelfat C, Rouleau GA (2003) Suicide and serotonin: study of variation at seven serotonin receptor genes in suicide completers. Am J Med Genet 118B:36–40CrossRefPubMedGoogle Scholar
  38. Zill P, Büttner A, Eisenmenger W, Möller H-J, Bondy B, Ackenheil M (2004) Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 56:581–586PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Idoia Martín-Guerrero
    • 1
  • Luis F. Callado
    • 2
  • Koldo Saitua
    • 1
  • Guadalupe Rivero
    • 2
  • África García-Orad
    • 1
  • J. Javier Meana
    • 2
    • 3
    Email author
  1. 1.Department of Genetics, Physical Anthropology and Animal PhysiologyUniversity of the Basque CountryLeioaSpain
  2. 2.Department of PharmacologyUniversity of the Basque CountryLeioaSpain
  3. 3.Departamento de FarmacologíaUniversidad del País Vasco / Euskal Herriko UnibertsitateaLeioaSpain

Personalised recommendations