, Volume 45, Issue 1, pp 60–66 | Cite as

The Other (Muscarinic) Acetylcholine Receptors in Sympathetic Ganglia: Actions and Mechanisms

  • D. A. Brown
Proceedings of the Symposium “Molecular Mechanisms of Regulation of Synaptic Transmission” (in Memory of V. I. Skok)

Acetylcholine released from preganglionic sympathetic fibers can activate two types of acetylcholine receptors in sympathetic neurons, nicotinic and muscarinic. The former are ligand-gated ion channels responsible for direct synaptic transmission; the latter are G protein-coupled receptors that mediate various indirect modulatory effects. Most mammalian sympathetic neurons express three muscarinic receptor subtypes, M1, M2, and M4; some also express M3 receptors. Activation of M1 receptors stimulates the G protein Gq and causes a slow postsynaptic depolarization and an increase in the excitability, ultimately leading to an asynchronous action potential discharge, which can “break through” the nicotinic ganglion block. This is largely mediated by closure of voltage-gated K+ channels (the M channels) composed of Kv7.2 and Kv7.3 subunits and results from hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate. Activation of M2 receptors hyperpolarizes and inhibits the postsynaptic neuron by opening G protein-gated inwardlyrectifying Kir K+ channels via the G protein Gi. M4 receptors inhibit N-type (CaV(2)) calcium channels via the G protein Go. In the postganglionic neuron somata, this enhances the excitability by reducing calcium-dependent potassium currents. Conversely, in postganglionic processes and axon terminals, CaV(2)-mediated inhibition reduces norepinephrine release and inhibits postganglionic transmission. Different muscarinic receptors may be anatomically segregated with their cognate G proteins and (in some cases) ion channels in signalling microdomains.


acetylcholine muscarinic receptors ion channels G protein phosphatidylinositol-4 5-bisphosphate microdomain 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    K. Kuba and K. Koketsu, “Synaptic events in sympathetic ganglia,” Prog. Neurobiol., 11, 77–169 (1978).PubMedCrossRefGoogle Scholar
  2. 2.
    T. Takeshige and R. L. Volle, “Bimodal responses of sympathetic ganglia to acetylcholine following serine or repetitive preganglionic stimulation,” J. Pharmacol. Exp. Ther., 138, 66–73 (1962).PubMedGoogle Scholar
  3. 3.
    A. M. Brown, “Cardiac sympathetic adrenergic pathways in which synaptic transmission is blocked by atropine sulfate,” J. Physiol., 191, 271–288 (1967).PubMedGoogle Scholar
  4. 4.
    W. Flacke and R. A. Gillis, “Impulse transmission via nicotinic and muscarinic pathways in the stellate ganglion of the dog,” J. Pharmacol. Exp. Ther., 163, 266–276 (1968).PubMedGoogle Scholar
  5. 5.
    D. A. Brown, “The Skok legacy and beyond: molecular mechanisms of slow synaptic excitation in sympathetic ganglia,” Neurophysiology/Neurofiziologiya, 39, 284–289 (2007).Google Scholar
  6. 6.
    D. A. Brown and A. A. Selyanko, “Membrane currents underlying the slow excitatory post-synaptic potential in the rat sympathetic ganglion,” J. Physiol., 365, 335–364 (1985).Google Scholar
  7. 7.
    D. A. Brown, N. J. Buckley, M. P. Caulfield, et al., “Coupling of muscarinic acetylcholine receptors to neural ion channels: closure of K+ channels,” in: Molecular Mechanisms of Muscarinic Acetylcholine Receptor Function, J. Wess (ed.), R. G. Landes Comp., Austin, TX (1995), pp. 165–182.Google Scholar
  8. 8.
    M. P. Caulfield and N. J. Birdsall, “International Union of Pharmacology XVII, Classification of muscarinic acetylcholine receptors,” Pharmacol. Rev., 50, 279–290 (1998).PubMedGoogle Scholar
  9. 9.
    N. V. Marrion, T. G. Smart, S. J. Marsh, and D. A. Brown, “Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype,” Br. J. Pharmacol., 98, 557–573 (1989).PubMedCrossRefGoogle Scholar
  10. 10.
    L. Bernheim, A. Mathie, and B. Hille, “Characterization of muscarinic receptor subtypes inhibiting Ca2+ current and M current in rat sympathetic neurons,” Proc. Natl. Acad. Sci. USA, 89, 9544–9548 (1992).PubMedCrossRefGoogle Scholar
  11. 11.
    S. E. Hamilton, M. D. Loose, M. Qi, et al., “Disruption of the m1 receptor gene ablates muscarinic receptordependent M current regulation and seizure activity in mice,” Proc. Natl. Acad. Sci. USA, 94, 13311–13316 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    D. A. Brown and P. R. Adams, “Muscarinic suppression of a novel voltage-sensitive K+-current in a vertebrate neuron,” Nature, 283, 673–676 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    H.-S. Wang, Z. Pan, W. Shi, et al., “KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel,” Science, 282, 1890–1893 (1998).PubMedCrossRefGoogle Scholar
  14. 14.
    J. K. Hadley, G. M. Passmore, L. Tatulian, et al., “Stoichiometry of expressed KCNQ2/KCNQ3 channels and subunit composition of native ganglionic M-channels deduced from block by tetraethylammonium (TEA),” J. Neurosci., 23, 5012–5019 (2003).PubMedGoogle Scholar
  15. 15.
    D. A. Brown, “Slow cholinergic excitation – a mechanism for increasing neuronal excitability,” Trends Neurosci., 6, 302–306 (1983).CrossRefGoogle Scholar
  16. 16.
    M. M. Shah, M. Migliore, M. I. Valencia, et al., “Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons,” Proc. Natl. Acad. Sci. USA, 105, 7869–7874 (2008).PubMedCrossRefGoogle Scholar
  17. 17.
    P. Delmas and D. A. Brown, “Pathways modulating neural KCNQ/M (Kv7) potassium channels,” Nat. Rev. Neurosci., 6, 850–862 (2005).PubMedCrossRefGoogle Scholar
  18. 18.
    H. Zhang, L. C. Craciun, T. Mirshahi, et al., “PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents,” Neuron, 37, 963–975 (2003).PubMedCrossRefGoogle Scholar
  19. 19.
    Y. Li, N. Gamper, D. W. Hilgemann, and M. S. Shapiro, “Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate,” J. Neurosci., 25, 9825–9835 (2005).PubMedCrossRefGoogle Scholar
  20. 20.
    B. C. Suh, L. F. Horowitz, W. Hirdes, et al., “Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq,” J. Gen. Physiol., 123, 663–683 (2004).PubMedCrossRefGoogle Scholar
  21. 21.
    J. S. Winks, J. Hughes, A. K. Filippov, et al., “Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels,” J. Neurosci., 25, 3400–3413 (2005).PubMedCrossRefGoogle Scholar
  22. 22.
    C. C. Hernandez, B. Falkenburger, and M. S. Shapiro, “Affinity for phosphatidylinositol 4,5-bisphosphate determines muscarinic agonist sensitivity of Kv7 K+ channels,” J. Gen. Physiol., 134, 437–448 (2009).PubMedCrossRefGoogle Scholar
  23. 23.
    V. Telezhkin, D. A. Brown, and A. J. Gibb, “Distinct subunit contributions to the activation of M-type potassium channels by PI(4,5)P2,” J. Gen. Physiol., 140, 41–53 (2012).PubMedCrossRefGoogle Scholar
  24. 24.
    P. Delmas, D. F. C. Abogadie, M. Dayrell, et al., “G-proteins and G-protein subunits mediating cholinergic inhibition of N-type calcium currents in sympathetic neurons,” Eur. J. Neurosci., 10, 1654–1666 (1998).PubMedCrossRefGoogle Scholar
  25. 25.
    D. S. Koh and B. Hille, “Modulation by neurotransmitters of catecholamine secretion from sympathetic ganglion neurons detected by amperometry,” Proc. Natl. Acad. Sci. USA, 94, 1506–1511 (1997).PubMedCrossRefGoogle Scholar
  26. 26.
    D. A. Brown, “M Сurrents,” Ion Channels, Vol. 1, T. Narahashi (ed.), Plenum Press, New York (1988), pp. 55–99.Google Scholar
  27. 27.
    N. Gamper, V. Reznikov, Y. Yamada, et al., “Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels,” J. Neurosci., 24, 10980–10992 (2004).PubMedCrossRefGoogle Scholar
  28. 28.
    J. E. Haley, F. C. Abogadie, P. Delmas, et al., “The alpha subunit of Gq contributes to muscarinic inhibition of the M-type potassium current in sympathetic neurons,” J. Neurosci., 18, 4521–4531 (1998).PubMedGoogle Scholar
  29. 29.
    D. A. Brown, “M-current: from discovery to single channel currents,” in: Slow Synaptic Reponses and Modulation, K. Kuba, H. Higashida, D. A. Brown, and T. Yoshioka (eds.), Springer, Tokyo (2000), pp. 15–26.CrossRefGoogle Scholar
  30. 30.
    H. Higashida, M. Hashii, K. Fukuda, et al., “Selective coupling of different muscarinic acetylcholine receptors to neuronal calcium currents in DNA-transfected cells,” Proc. Biol. Sci., 242, 68–74 (1990).PubMedCrossRefGoogle Scholar
  31. 31.
    M. S. Shapiro, M. D. Loose, S. E. Hamilton, et al., “Assignement of muscarinic receptor subtypes mediating G-protein modulation of Ca 21 channels by using knockout mice,” Proc. Natl. Acad. Sci. USA, 96, 10899–10904 (1999).PubMedCrossRefGoogle Scholar
  32. 32.
    T. G. Allen and D. A. Brown, “M2 muscarinic receptor-mediated inhibition of the Ca2+ current in rat magnocellular cholinergic basal forebrain neurons,” J. Physiol., 466, 173–189 (1993).PubMedGoogle Scholar
  33. 33.
    J. M. Fernandez-Fernandez, N. Wanaverbecq, P. Halley, et al., “A role for M2 receptors in the muscarinic activation of G protein-gated K+ (GIRK) channels expressed in isolated rat sympathetic neurons,” J. Physiol., 515, 631–637 (1999).PubMedCrossRefGoogle Scholar
  34. 34.
    J. M. Fernandez-Fernandez, F. C. Abogadie, G. Milligan, et al., “Multiple pertussis toxin-sensitive G proteins can couple receptors to GIRK channels in rat sympathetic neurons when heterologously-expressed, but only native Gi proteins do so in situ,” Eur. J. Neurosci., 14, 283–292 (2001).PubMedCrossRefGoogle Scholar
  35. 35.
    J. Dodd and J. P. Horn, “Muscarinic inhibition of sympathetic C neurons in the bullfrog,” J. Physiol., 334, 271–291 (1983).PubMedGoogle Scholar
  36. 36.
    H. Cruzblanca, D. S. Koh, and B. Hille, “Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons,” Proc. Natl. Acad. Sci. USA, 95, 7151–7156 (1998).PubMedCrossRefGoogle Scholar
  37. 37.
    P. Delmas, N. Wanaverbecq, F. C. Abogadie, et al., “Signaling microdomains define the specificity of receptor-mediated InsP(3) pathways in neurons,” Neuron, 34, 209–220 (2002).PubMedCrossRefGoogle Scholar
  38. 38.
    O. Zaika, J. Zhang, and M. S. Shapiro, “Combined phosphoinositide and Ca2+ signals mediating receptor specificity toward neuronal Ca2+ channels,” J. Biol. Chem., 286, 830–841 (2011).PubMedCrossRefGoogle Scholar
  39. 39.
    N. Hoshi, J. S. Zhang, M. Omaki, et al., “AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists,” Nat. Neurosci., 6, 564–571 (2003).PubMedCrossRefGoogle Scholar
  40. 40.
    N. Hoshi, L. K. Langeberg, and J. D. Scott, “Distinct enzyme combinations in AKAP signalling complexes permit functional diversity,” Nat. Cell Biol., 7, 1066–1073 (2005).PubMedCrossRefGoogle Scholar
  41. 41.
    J. Zhang. M. Bal, S. Bierbower, et al., “AKAP79/150 signal complexes in G-protein modulation of neuronal ion channels,” J. Neurosci., 31, 7199–7211 (2011).Google Scholar
  42. 42.
    A. Kosenko, S. Kang, I. M. Smith, et al., “Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation,” EMBO J., 31, 3147–3156 (2012).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Neuroscience, Physiology, and PharmacologyUniversity College LondonLondonGreat Britain

Personalised recommendations