Cellular and Molecular Neurobiology

, Volume 17, Issue 1, pp 35–50 | Cite as

Potency of Agonists and Competitive Antagonists on Adult- and Fetal-Type Nicotinic Acetylcholine Receptors

  • C. Spencer Yost
  • Bruce D. Winegar


1. The potency of agonists and competitive antagonists on the two expressed forms of the nicotinic acetylcholine receptor (adult or junctional subtype, ε-AChR; fetal or extrajunctional subtype, γ-AChR) have not previously been compared systematically in homogeneous receptor preparations.

2. Each subtype of the receptor was expressed separately in Xenopus oocytes by cytoplasmic injection of combinations of RNA transcribed in vitro. The presence of each type of receptor was confirmed by single-channel recordings. Expressing oocytes were assayed using discontinuous, single-electrode voltage clamp by measuring peak currents in response to test compounds.

3. The extrajunctional subtype was more potently activated by the nicotinic agonist dimethylphenyl piperazinium iodide (DMPP) than was the junctional form. There was no statistically significant difference in potency between the two subtypes for other nicotinic agonists (nicotine, cytisine and succinylcholine). The rank order of potency for ε-AChR was succinylcholine>cytisine>DMPP>nicotine, and that for γ-AChR was DMPP>cytisine>succinylcholine>nicotine.

4. Two agonists (cytisine and succinylcholine) displayed six- to eight-fold greater intrinsic activity in activating ε-AChR over γ-AChR. There was no difference between the two forms of receptor in efficacy for nicotine.

5. The extrajunctional form was much more potently inhibited by the steroidal competitive antagonist pancuronium than was the junctional receptor. However, there was no significant difference in potency of inhibition by the curariform drug atracurium.

6. Contrary to previous reports, there is no consistent relation between the effect of agonists and antagonists and the subtype of receptor. These data suggest that the resistance or sensitivity to these agents seen in various clinical settings are related to other cellular factors.

acetylcholine receptor agonists nondepolarizing muscle relaxants extrajunctional receptor neuromuscular junction voltage clamp oocytes 


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  1. Bouzat, C., Bren, N., and Sine, S. M. (1994). Structural basis of the different gating kinetics of fetal and adult acetylcholine receptors. Neuron 13:1295–402.Google Scholar
  2. Bowmann, W. C. (1990). Pharmacology of Neuromuscular Function, Wright, London.Google Scholar
  3. Changeux, J.-P., Benoit, P., Bessis, A., Cartaud, J., Devillers-Thierry, A., Fontaine, B., Galzi, J. L., Klarsfeld, A., Laufer, R., and Mulle, C. (1990). The acetylcholine receptor: Functional architecture and regulation. Adv. Sec. Mess. Phospro. Res. 24:15–23.Google Scholar
  4. Dascal, N. (1987). The use of Xenopus oocytes for the study of ion channels. CRC Crit. Rev. Biochem. 22:317–383.Google Scholar
  5. Fu, D. X., and Sine, S. M. (1994). Competitive antagonists bridge the alpha-gamma subunit interface of the acetylcholine receptor through quaternary ammonium-aromatic interactions. J. Biol. Chem. 269:26152–26157.Google Scholar
  6. Goldman, D., Brenner, H. R., and Heinemann, S. (1988). Acetylcholine receptor alpha-, beta-, gamma-, and delta-subunit mRNA levels are regulated by muscle activity. Neuron 1:329–333.Google Scholar
  7. Goldman, D., and Staple, J. (1989). Spatial and temporal expression of acetylcholine receptor RNAs in innervated and denervated rat soleus muscle. Neuron 3:219–228.Google Scholar
  8. Gu, Y., and Hall, Z. W. (1988a). Characterization of acetylcholine receptor subunits in developing and in denervated mammalian muscle. J. Biol. Chem. 263:12878–12885.Google Scholar
  9. Gu, Y., and Hall, Z. W. (1988b). Immunological evidence for a change in subunits of the acetylcholine receptor in developing and denervated rat muscle. Neuron 1:117–125.Google Scholar
  10. Gu, Y., Franco, A., Gardner, P. D., Lansman, J. B., Forsayeth, J. R., and Hall, Z. W. (1990). Properties of embryonic and adult muscle acetylcholine receptors transiently expressed in COS cells. Neuron 5:147–157.Google Scholar
  11. Gundersen, C. B., Miledi, R., and Parker, I. (1984). Messenger RNA from human brain induces drug-and voltage-operated channels in Xenopus oocytes. Nature 308:421–424.Google Scholar
  12. Katz, B., and Miledi, R. (1972). The statistical nature of the acetylcholine potential and its molecular components. J. Physiol. (Lond). 224:665–699.Google Scholar
  13. Kopta, C., and Steinbach, J. H. (1994). Comparison of mammalian adult and fetal nicotinic acetylcholine receptors stably expressed in fibroblasts. J. Neurosci. 14:3922–3993.Google Scholar
  14. Lingle, C. J., Maconochie, D., and Steinbach, J. H. (1992). Activation of skeletal muscle nicotinic acetylcholine receptors. J. Membr. Biol. 126:195–217.Google Scholar
  15. Luetje, C. W., and Patrick, J. (1991). Both alpha-and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors. J. Neurosci. 11:837–845.Google Scholar
  16. Martyn, J. A., White, D. A., Gronert, G. A., Jaffe, R. S., and Ward, J. M. (1992). Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers. Anesthesiology 76:822–843.Google Scholar
  17. Melton, D. (1984). Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acid Res. 12:7035–7056.Google Scholar
  18. Mishina, M., Takai, T., Imoto, K., Noda, M., Takahashi, T., Numa, S., Methfessel, C., and Sakmann, B. (1986). Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature 321:406–411.Google Scholar
  19. Moorthy, S. S., and Hilgenberg, J. C. (1980). Resistance to non-depolarizing muscle relaxants in paretic upper extremities of patients with residual hemiplega. Anesth. Analg. 59:624–627.Google Scholar
  20. Salpeter, M. M., and Marchaterre, M. (1992). Acetylcholine receptors in extrajunctional regions of innervated muscle have a slow degradation rate. J. Neurosci. 12:35–38.Google Scholar
  21. Sine, S. M. (1993). Molecular dissection of subunit interfaces in the acetylcholine receptor: Identification of residues that determine curare selectivity. Proc. Natl. Acad. Sci. USA 90:9436–9440.Google Scholar
  22. Sine, S. M., and Claudio, T. (1991). Gamma-and delta-subunits regulate the affinity and the cooperativity of ligand binding to the acetylcholine receptor. J. Biol. Chem. 266:19369–19377.Google Scholar
  23. Steinbach, J. H., and Chen, Q. (1995). Antagonist and partial agonist actions of d-turocurarine at mammalian muscle acetylcholine receptors. J. Neurosci. 15:230–240.Google Scholar
  24. Stroud, R. M., McCarthy, M. P., and Shuster, M. (1990). Nicotinic acetylcholine receptor superfamily of ligand-gated ion channels. Biochemistry 29:11009–11023.Google Scholar
  25. Theroux, M. C., Brandom, B. W., Zagnoev, M., Kettrick, R. G., Miller, F., and Ponce, C. (1994). Dose response of succinylcholine at the adductor pollicis of children with cerebal palsy during propofol and nitrous oxide anesthesia. Anesth. Analg. 79:761–765.Google Scholar
  26. Unwin, N. (1993). Nicotonic acetylcholine receptor at 9 A resolution. J. Mol. Biol. 229:1101–1124.Google Scholar
  27. Unwin, N. (1995). Acetylcholine receptor channel imaged in the open state. Nature 373:37–43.Google Scholar
  28. Witzemann, V., Barg, B., Criado, M., Stein, E., and Sakmann, B. (1989). Developmental regulation of five subunit specific mRNAs encoding acetylcholine receptor subtypes in rat muscle. FEBS Lett. 242:419–424.Google Scholar
  29. Yost, C. A., and Dodson, B. A. (1993). Inhibition of the nicotinic acetylcholine receptor by barbiturates and by procaine: Do they act at different sites? Cell. Mol. Neurobiol. 13:159–172.Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • C. Spencer Yost
    • 1
  • Bruce D. Winegar
    • 1
  1. 1.Department of Anesthesia, Medical Sciences 255University of CaliforniaSan Francisco

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