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Journal of Molecular Neuroscience

, Volume 27, Issue 2, pp 185–194 | Cite as

Inhibition of ligand binding to g protein-coupled receptors by arachidonic acid

  • Elizabeth Z. Bordayo
  • John R. Fawcett
  • Sarita Lagalwar
  • Aleta L. Svitak
  • William H. FreyEmail author
Original Article

Abstract

Arachidonic acid (AA), released in response to muscarinic acetylcholine receptor (mAChR) stimulation, previously has been reported to function as a reversible feedback inhibitor of the mAChR. To determine if the effects of AA on binding to the mAChR are subtype specific and whether AA inhibits ligand binding to other G protein-coupled receptors (GPCRs), the effects of AA on ligand binding to the mAChR subtypes (M1, M2, M3, M4, and M5) and to the μ-opioid receptor, β2-adrenergic receptor (β2-AR), 5-hydroxytryptamine receptor (5-HTR), and nicotinic receptors were examined. AA was found to inhibit ligand binding to all mAChR subtypes, to the β2-AR, the 5-HTR, and to the μ-opioid receptor. However, AA does not inhibit ligand binding to the nicotinic receptor, even at high concentrations of AA. Thus, AA inhibits several types of GPCRs, with 50% inhibition occurring at 3–25 µM, whereas the nicotinic receptor, a non-GPCR, remains unaffected. Further research is needed to determine the mechanism by which AA inhibits GPCR function.

Index Entries

Arachidonic acid G protein-coupled receptors feedback inhibition muscarinic receptor fatty acids 

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References

  1. Berzaghi M. P., Cooper J., Castren E., Zafra F., Sofroniew M., et al. (1993) Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus. J. Neurosci. 13, 3818–3826.Google Scholar
  2. Cakir Y., Plummer H. K. III, Tithof P. K., and Schuller H. M. (2002) Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int. J. Oncol. 21, 153–157.PubMedGoogle Scholar
  3. Chalimoniuk M., King-Pospisil K., Pedersen W. A., Malecki A., Wylegala E., Mattson M. P., et al. (2004) Arachidonic acid increases choline acetyltransferase activity in spinal cord neurons through a protein kinase C-mediated mechanism. J. Neurochem. 90, 629–636.PubMedCrossRefGoogle Scholar
  4. Christopoulos A. and Kenakin T. (2002) G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54, 323–374.PubMedCrossRefGoogle Scholar
  5. Conklin B. R., Brann M. R., Buckley N. J., Ma A. L., Bonner T. I., and Axelrod J. (1988) Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells. Proc. Natl. Acad. Sci. U. S. A. 85, 8698–8702.PubMedCrossRefGoogle Scholar
  6. Cunha R. A., Constantino M. D., Fonseca E., and Ribeiro J. A. (2001) Age-dependent decrease in adenosine A1 receptor binding sites in the rat brain. Eur. J. Biochem. 268, 2939–2947.PubMedCrossRefGoogle Scholar
  7. Cunha R. A., Ribeiro J. A., and Malva J. O. (2004) Presynaptic kainate receptors modulating glutamatergic transmission in the rat hippocampus are inhibited by arachidonic acid. Neurochem. Int. 44, 371–379.PubMedCrossRefGoogle Scholar
  8. Davies P. and Maloney A. J. F. (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 2, 1403.PubMedCrossRefGoogle Scholar
  9. Devane W. A. and Axelrod J. (1994) Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc. Natl. Acad. Sci. U. S. A. 91, 6698–6701.PubMedCrossRefGoogle Scholar
  10. Farias G. G., Godoy J. A., Hernandez F., Avila J., Fisher A., and Inestrosa N. C. (2004) M1 muscarinic receptor activation protects neurons from β-amyloid toxicity. A role for Wnt signaling pathway. Neurobiol. Dis. 17, 337–348.PubMedCrossRefGoogle Scholar
  11. Fawcett J. R., Bordayo E. Z., Jackson K., Liu H., Peterson J., Svitak A., and Frey W. H. II (2002) Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer’s brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants. Brain Res. 950, 10–20.PubMedCrossRefGoogle Scholar
  12. Felder C. C., Kanterman R. Y., Ma A. L., and Axelrod J. (1990) Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2-serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc. Natl. Acad. Sci. U. S. A. 87, 2187–2191.PubMedCrossRefGoogle Scholar
  13. Fukuda K., Kato S., Morikawa H., Shoda T., and Mori K. (1996) Functional coupling of the δ-, μ-, and κ, opioid receptors to mitogen-activated protein kinase and arachidonate release in Chinese hamster ovary cells. J. Neurochem. 67, 1309–1316.CrossRefGoogle Scholar
  14. Glick J., Santoyo G., and Casey P. J. (1996) Arachidonate and related unsaturated fatty acids selectively inactivate the guanine nucleotide-binding regulatory protein, Gz. J. Biol. Chem. 271, 2949–2954.Google Scholar
  15. Jensen A. A. and Spalding T. A. (2004) Allosteric modulation of G-protein coupled receptors. Eur. J. Pharmacol. Sci. 21, 407–420.CrossRefGoogle Scholar
  16. Kim J., Isokawa M., Ledent C., and Alger B. E. (2002) Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J. Neurosci. 22, 10182–10191.PubMedGoogle Scholar
  17. Kimura T., Ohta T., Watanabe K., Yoshimura H., and Yamamoto I. (1998) Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5-hydroxytryptamine (5-HT) receptor. Biol. Pharm. Bull. 21, 224–226.PubMedGoogle Scholar
  18. King M. E., Gamblin T. C., Kuret J., and Binder L. I. (2000) Differential assembly of human tau isoforms in the presence of arachidonic acid. J. Neurochem. 74, 1749–1757.PubMedCrossRefGoogle Scholar
  19. Kirstein S. L. and Insel P. A. (2004) Autonomic nervous system pharmacogenomics: a progress report. Pharmcol. Rev. 56, 31–52.CrossRefGoogle Scholar
  20. Kjome J. R., Swenson K. A., Johnson M. N., Bordayo E. Z., Anderson L. E., Klevan A. I., et al. (1998) Inhibition of antagonist and agonist binding to the human brain muscarinic receptor by arachidonic acid. J. Mol. Neurosci. 10, 209–217.PubMedCrossRefGoogle Scholar
  21. Lagalwar S., Bordayo E. Z., Hoffmann K. L., Fawcett J. R., and Frey W. H. II (1999) Anandamides inhibit binding to the muscarinic acetylcholine receptor. J. Mol. Neurosci. 13, 55–62.PubMedCrossRefGoogle Scholar
  22. Leggett J. D., Aspley S., Beckett S. R. G., D’ Antona A. M., and Kendall D. A. (2004) Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br. J. Pharmacol. 141, 253–262.PubMedCrossRefGoogle Scholar
  23. Levey A. I. (1996) Muscarinic acetylcholine receptor expression in memory circuits: implication of treatment of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 93, 13541–13546.CrossRefGoogle Scholar
  24. Liu L., Roberts M. L. and Rittenhouse A. R. (2004) Phospholipid metabolism is required for M1 muscarinic inhibition of N-type calcium current in sympathetic neurons. Eur. Biophys. J. 33, 255–264.PubMedCrossRefGoogle Scholar
  25. Lorenzini A., Hrelia S., Bordoni A., Biagi P., Frisoni L., Marinucci T., Cristofalo V. J. (2001) Is increased arachidonic acid release a cause or a consequence of replicative senescence? Exp. Gerontol. 36, 65–78.PubMedCrossRefGoogle Scholar
  26. Marks M. J. and Collins A. C. (1982) Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate. Mol. Pharmacol. 22, 554–564.PubMedGoogle Scholar
  27. Menzaghi F., Behan D. P., and Chalmers D. T. (2002) Constitutively activated G- protein coupled receptors: a novel approach to CNS drug discovery. CNS Neurol. Dis. 1, 105–121.CrossRefGoogle Scholar
  28. Oktem H. A. and Apaydin S. (1998) Arachidonic acid modulation of 3H-naloxone specific binding to rat brain opioid receptors. Neurobiology 6, 323–332.PubMedGoogle Scholar
  29. Rodriguez-Puertas R., Pascual R. J., Vilaro T., and Pazos A. (1997) Autoradiographic distribution of M1, M2, M3, and M4 muscarinic receptor subtypes in Alzheimer’s disease. Synapse 26, 341–350.PubMedCrossRefGoogle Scholar
  30. Rosenblum K., Futter M., Jones M., Hulme E. C., and Bliss T. V. P. (2000) ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. J. Neurosci. 20, 977–985.PubMedGoogle Scholar
  31. Saitoh H., Namatame Y., Hirano A., and Sugawara M. (2004) An excised patch membrane sensor for arachidonic acid released in mouse hippocampal slices under stimulation of L-glutamate. Anal. Biochem. 329, 163–172.PubMedCrossRefGoogle Scholar
  32. Sato T., Hashizume T., Nakao K., Akiba S., and Fujii T. (1989) Platelet desensitization by arachidonic acid is associated with the suppression of end operoxide/thromboxane A2 binding to the membrane receptor. Biochim. Biophys. Acta 992, 168–173.PubMedGoogle Scholar
  33. Scarpero H. M. and Dmochowski R. R. (2003) Muscarinic receptors: what we know. Curr. Urol. Rep. 4, 421–428.PubMedCrossRefGoogle Scholar
  34. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzane M. D., et al. (1985) Measurement of protein using bicinchonic acid. Ann. Biochem. 150, 76–85.CrossRefGoogle Scholar
  35. Thomas E. A., Carson M. J., Neal M. J., and Sutcliffe G. (1997) Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal transduction by oleamide. Proc. Natl. Acad. Sci. U. S. A. 94, 14115–14119.PubMedCrossRefGoogle Scholar
  36. van Koppen C. J. and Bjorn K. (2003) Regulation of muscarinic acetylcholine receptor signaling. Pharmacol. Ther. 98, 197–220.PubMedCrossRefGoogle Scholar
  37. Whitehouse P.J., Price D. L., Struble R. G., Clark A. W., Coyle J. T., and DeLong M. R. (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239.PubMedCrossRefGoogle Scholar
  38. Xu H., Lichtstein D., Kassis S., Lutz R. A., Rodbard D., and Chernick S. S. (1988) Multiple interactions of unsaturated fatty acids with opiate and ouabain binding sites and β-adrenergic sensitive adenylate cyclase system. J. Recept. Res. 8, 205–223.PubMedGoogle Scholar
  39. Yasuda H., Kishiro K., Izumi N., and Nakanishi M. (1985) Biphasic liberation of arachidonic and stearic acids during cerebral ischemia. 45, 168–172.Google Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Elizabeth Z. Bordayo
    • 1
  • John R. Fawcett
    • 1
  • Sarita Lagalwar
    • 1
  • Aleta L. Svitak
    • 1
  • William H. Frey
    • 1
    Email author
  1. 1.Alzheimer’s Research CenterHealthPartners Research FoundationSaint Paul

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