Skip to main content
Log in

John Daly’s Compound, Epibatidine, Facilitates Identification of Nicotinic Receptor Subtypes

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The diversity of nicotinic acetylcholine receptor (nAChR) subtypes was explored by measuring the effects of gene deletion and pharmacological diversity of epibatidine binding sites in mouse brain. All epibatidine binding sites require expression of either the α7, β2, or β4 subunit. In agreement with general belief, the α4β2*-nAChR and α7-nAChR subtypes are major components of the epibatidine binding sites. α4β2*-nAChR sites account for approximately 70% of total high- and low-affinity epibatidine binding sites, while α7-nAChR accounts for 16% of the total sites all of which have lower affinity for epibatidine. The other subtypes are structurally diverse. Although these minor subtypes account for only 14% of total binding in whole brain, they are expressed at relatively high concentrations in specific brain areas indicating unique functional roles.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Abood, L. G., & Grassi, S. (1986). [3H]Methylcarbamylcholine, a new radioligand for studying brain nicotinic receptors. Biochemical Pharmacology, 35, 4199–4202.

    Article  CAS  PubMed  Google Scholar 

  • Adams, M. R., Nikkel, A. L., Donnelly-Roberts, D. L., Watt, A. T., Johnston, J. F., Cowsert, L. M., et al. (2004). In vitro and in vivo effects of an alpha3 neuronal nicotinic acetylcholine receptor antisense oligonucleotide. Brain Research. Molecular Brain Research, 129, 67–79.

    Article  CAS  PubMed  Google Scholar 

  • Anderson, D. J., & Arneric, S. P. (1994). Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain. European Journal of Pharmacology, 253, 261–267.

    Article  CAS  PubMed  Google Scholar 

  • Badio, B., & Daly, J. W. (1994). Epibatidine, a potent analgetic and nicotinic agonist. Molecular Pharmacology, 45, 563–569.

    CAS  PubMed  Google Scholar 

  • Brown, R. W., Collins, A. C., Lindstrom, J. M., & Whiteaker, P. (2007). Nicotinic alpha5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers. Journal of Neurochemistry, 103, 204–215.

    CAS  PubMed  Google Scholar 

  • Champtiaux, N., Gotti, C., Cordero-Erausquin, M., David, D. J., Przybylski, C., Léna, C., et al. (2003). Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. Journal of Neuroscience, 23, 7820–78299.

    CAS  PubMed  Google Scholar 

  • Clarke, P. B. S., Schwartz, R. D., Paul, S. M., Pert, C. B., & Pert, A. (1985). Nicotinic binding in rat brain: Autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. Journal of Neuroscience, 5, 1307–1315.

    CAS  PubMed  Google Scholar 

  • Collins, A. C., Salminen, O., Marks, M. J., Whiteaker, P., & Grady, S. R. (2009). The road to discovery of nicotinic receptor subtypes. Handbook of Experimental Pharmacology, 192, 85–112.

    Article  PubMed  Google Scholar 

  • Conroy, W. G., & Berg, D. K. (1995). Neurons can maintain multiple classes of nicotinic acetylcholine receptors distinguished by different subunit compositions. Journal of Biological Chemistry, 270, 4424–4431.

    Article  CAS  PubMed  Google Scholar 

  • Cox, B. C., Marritt, A. M., Perry, D. C., & Kellar, K. J. (2008). Transport of multiple nicotinic acetylcholine receptors in the rat optic nerve: High densities of receptors containing alpha6 and beta3 subunits. Journal of Neurochemistry, 105, 1924–1938.

    Article  CAS  PubMed  Google Scholar 

  • Daly, J. W., Brown, G. B., Mennah-Dwumah, H., & Myers, C. W. (1978). Classification of skin alkaloids from neotropical poison-dart frogs (Dendrobatidae). Toxicon, 16, 163–188.

    Article  CAS  PubMed  Google Scholar 

  • Dávila-García, M. I., Musachio, J. L., Perry, D. C., Xiao, Y., Horti, A., London, E. D., et al. (1997). [125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors. Journal of Pharmacology and Experimental Therapeutics, 282, 445–451.

    PubMed  Google Scholar 

  • Gerzanich, V., Peng, X., Wang, F., Wells, G., Anand, R., Fletcher, S., et al. (1995). Comparative pharmacology of epibatidine: A potent agonist for neuronal nicotinic acetylcholine receptors. Molecular Pharmacology, 48, 774–782.

    CAS  PubMed  Google Scholar 

  • Gotti, C., Moretti, M., Zanardi, A., Gaimarri, A., Champtiaux, N., Changeux, J. P., et al. (2005a). Heterogeneity and selective targeting of neuronal nicotinic acetylcholine receptor (nAChR) subtypes expressed on retinal afferents of the superior colliculus and lateral geniculate nucleus: Identification of a new native nAChR subtype alpha3beta2(alpha5 or beta3) enriched in retinocollicular afferents. Molecular Pharmacology, 68, 1162–1171.

    Article  CAS  PubMed  Google Scholar 

  • Gotti, C., Moretti, M., Clementi, F., Riganti, L., McIntosh, J. M., Collins, A. C., et al. (2005b). Expression of nigrostriatal alpha 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion. Molecular Pharmacology, 67, 2007–2015.

    Article  CAS  PubMed  Google Scholar 

  • Grady, S. R., Moretti, M., Zoli, M., Marks, M. J., Zanardi, A., Pucci, L., et al. (2009). Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release. Journal of Neuroscience, 29, 2272–2282.

    Article  CAS  PubMed  Google Scholar 

  • Houghtling, R. A., Davila-Garcia, M. I., Hurt, S. D., & Kellar, K. J. (1994). [3H]Epibatidine binding to nicotinic cholinergic receptors in brain. Medicinal Chemistry Research, 4, 538–546.

    CAS  Google Scholar 

  • Houghtling, R. A., Davila-Garcia, M. I., Hurt, S. D., & Kellar, K. J. (1995). Characterization of [3H]epibatidine binding to nicotinic cholinergic receptors in rat and human brain. Molecular Pharmacology, 48, 280–287.

    CAS  PubMed  Google Scholar 

  • Mao, D., Yasuda, R. P., Fan, H., Wolfe, B. B., & Kellar, K. J. (2006). Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose ganglia. Molecular Pharmacology, 70, 1693–1699.

    Article  CAS  PubMed  Google Scholar 

  • Marks, M. J., & Collins, A. C. (1982). Characterization of nicotine binding in mouse brain and comparison with the binding of α-bungarotoxin and quinuclidinyl benzilate. Molecular Pharmacology, 22, 554–564.

    CAS  PubMed  Google Scholar 

  • Marks, M. J., Smith, K. W., & Collins, A. C. (1998). Differential agonist inhibition identifies multiple epibatidine binding sites in mouse brain. Journal of Pharmacology and Experimental Therapeutics, 285, 377–386.

    CAS  PubMed  Google Scholar 

  • Marks, M. J., Whiteaker, P., Calcaterra, J., Stitzel, J. A., Bullock, A. E., Grady, S. R., et al. (1999). Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the β2 subunit. Journal of Pharmacology and Experimental Therapeutics, 289, 1090–1103.

    CAS  PubMed  Google Scholar 

  • Marks, M. J., Whiteaker, P., Grady, S. R., Picciotto, M. R., McIntosh, J. M., & Collins, A. C. (2002). Characterization of [125I]epibatidine binding and nicotinic agonist-mediated 86Rb+ efflux in interpeduncular nucleus and inferior colliculus of β2 null mutant mice. Journal of Neurochemistry, 81, 1102–1115.

    Article  CAS  PubMed  Google Scholar 

  • Marks, M. J., Whiteaker, P., & Collins, A. C. (2006). Deletion of the α7, β2 or β4 nicotinic receptor subunit genes identifies highly expressed subtypes with relatively low affinity for [3H]epibatidine. Molecular Pharmacology, 70, 947–959.

    Article  CAS  PubMed  Google Scholar 

  • Marks, M. J., Meinerz, N. M., Drago, J., & Collins, A. C. (2007). Gene targeting demonstrates that α4 nicotinic acetylcholine receptor subunits contribute to the expression of diverse [3H]epibatidine binding sites and components of biphasic 86Rb+ efflux with high and low sensitivity to stimulation by acetylcholine. Neuropharmacology, 53, 390–405.

    Article  CAS  PubMed  Google Scholar 

  • Marritt, A. M., Cox, B. C., Yasuda, R. P., McIntosh, J. M., Xiao, Y., Wolfe, B. B., et al. (2005). Nicotinic cholinergic receptors in the rat retina: Simple and mixed heteromeric subtypes. Molecular Pharmacology, 68, 1656–1668.

    CAS  PubMed  Google Scholar 

  • Martino-Barrows, A. M., & Kellar, K. J. (1987). [3H]Acetylcholine and [3H](−)nicotine label the same recognition site in brain. Molecular Pharmacology, 31, 169–174.

    CAS  PubMed  Google Scholar 

  • Marubio, L. M., del Mar Arroyo-Jimenez, M., Cordero-Erausquin, M., Lena, C., Le Novere, N., de Kerchove d’Exaerde, A., et al. (1999). Nature (London), 398, 805–810.

    Article  CAS  Google Scholar 

  • Millar, N. S., & Gotti, C. (2008). Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology, 56, 237–246.

    Article  PubMed  Google Scholar 

  • Moroni, M., Zwart, R., Sher, E., Cassels, B. K., & Bermudez, I. (2006). α4β2 nicotinic receptors with high and low acetylcholine sensitivity: Pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine. Molecular Pharmacology, 70, 755–768.

    Article  CAS  PubMed  Google Scholar 

  • Orr-Urtreger, A., Goldner, F. M., Saeki, M., Lorenzo, T., Goldberg, T., DeBiasi, M., et al. (1997). Mice deficient in the α7 neuronal nicotinic receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. Journal of Neuroscience, 17, 9165–9171.

    CAS  PubMed  Google Scholar 

  • Pabreza, L. A., Dhawan, S., & Kellar, K. J. (1991). [3H]Cytisine binding to nicotinic cholinergic receptors in brain. Molecular Pharmacology, 39, 9–12.

    CAS  PubMed  Google Scholar 

  • Parker, M. J., Beck, A., & Leutje, C. W. (1998). Neuronal nicotinic receptor β2 and β4 subunits confer large differences in agonist binding affinity. Molecular Pharmacology, 54, 1132–1139.

    CAS  PubMed  Google Scholar 

  • Patrick, J., & Stallcup, W. B. (1977). α-Bungarotoxin binding and cholinergic receptor function on a rat sympathetic nerve cell line. Journal of Biological Chemistry, 252, 8629–8633.

    CAS  PubMed  Google Scholar 

  • Perry, D. C., & Kellar, K. J. (1995). [3H]Epibatidine labels nicotinic receptors in rat brain: An autoradiographic study. Journal of Pharmacology and Experimental Therapeutics, 275, 1030–1034.

    CAS  PubMed  Google Scholar 

  • Perry, D. C., Xiao, Y., Nguyen, H. N., Musachio, J. L., Dávila-García, M. I., & Kellar, K. J. (2002). Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. Journal of Neurochemistry, 82, 468–481.

    Article  CAS  PubMed  Google Scholar 

  • Picciotto, M. R., Zoli, M., Lena, C., Bessis, A., Lallemand, Y., LeNovere, N., et al. (1995). Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature, 374, 65–67.

    Article  CAS  PubMed  Google Scholar 

  • Pons, S., Fattore, L., Cossu, G., Tolu, S., Porcu, E., McIntosh, J. M., et al. (2008). Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. Journal of Neuroscience, 28, 12318–12327.

    Article  CAS  PubMed  Google Scholar 

  • Romano, C., & Goldstein, A. (1980). Stereospecific nicotine receptors on rat brain membranes. Science, 210, 647–650.

    Article  CAS  PubMed  Google Scholar 

  • Salas, R., Cook, K. D., Bassetto, L., & De Biasi, M. (2004). The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology., 47, 401–407. Erratum in: (2004) Neuropharmacology, 47, 1113.

    Article  CAS  PubMed  Google Scholar 

  • Salminen, O., Whiteaker, P., Grady, S. R., Collins, A. C., McIntosh, J. M., & Marks, M. J. (2005). The subunit composition and pharmacology of alpha-conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology, 48, 696–705.

    Article  CAS  PubMed  Google Scholar 

  • Salminen, O., Drapeau, J. A., McIntosh, J. M., Collins, A. C., Marks, M. J., & Grady, S. R. (2007). Pharmacology of α-conotoxin MII-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Molecular Pharmacology, 71, 1563–1571.

    Article  CAS  PubMed  Google Scholar 

  • Whiteaker, P., Jimenez, M., McIntosh, J. M., Collins, A. C., & Marks, M. J. (2000). Identification of a novel nicotinic binding site in mouse brain using [125I]-epibatidine. British Journal of Pharmacology, 131, 729–739.

    Article  CAS  PubMed  Google Scholar 

  • Whiteaker, P., Peterson, C. G., Xu, W., McIntosh, J. M., Paylor, R., Beaudet, A. L., et al. (2002). Involvement of the alpha3 subunit in central nicotinic binding populations. Journal of Neuroscience, 22, 2522–2529.

    CAS  PubMed  Google Scholar 

  • Zoli, M., Lena, C., Picciotto, M. R., & Changeux, J.-P. (1998). Identification of four classes of nicotinic receptors using beta2 mutant mice. Journal of Neuroscience, 18, 4461–4472.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael J. Marks.

Additional information

Supported by grants DA003194, DA012242, and DA015663 to ACC, MJM, and PW and GM048677 and MH053631 to JMM

Proceedings of the XIII International Symposium on Cholinergic Mechanisms

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marks, M.J., Laverty, D.S., Whiteaker, P. et al. John Daly’s Compound, Epibatidine, Facilitates Identification of Nicotinic Receptor Subtypes. J Mol Neurosci 40, 96–104 (2010). https://doi.org/10.1007/s12031-009-9264-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-009-9264-x

Keywords

Navigation