Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Oct 15;89(20):9544–9548. doi: 10.1073/pnas.89.20.9544

Characterization of muscarinic receptor subtypes inhibiting Ca2+ current and M current in rat sympathetic neurons.

L Bernheim 1, A Mathie 1, B Hille 1
PMCID: PMC50168  PMID: 1329101

Abstract

Muscarinic receptors mediating suppression of Ca2+ current and of M-type K+ current in rat superior cervical ganglion neurons were subclassified pharmacologically by using the muscarinic receptor antagonists pirenzepine and himbacine. Our voltage clamp experiments previously distinguished fast and slow intracellular signaling pathways coupling muscarinic receptors to calcium channels. We now establish that the fast, pertussis toxin-sensitive suppression of Ca2+ current is mediated primarily by muscarinic receptors of the M4 subtype, whereas the slow, bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetate (BAPTA)-sensitive suppression of Ca2+ current is mediated primarily by muscarinic receptors of the M1 subtype. Both actions on Ca2+ current are blocked by guanosine 5'-[beta-thio]diphosphate. Muscarinic suppression of M current is slow, BAPTA-sensitive, and mediated by receptors of the M1 subtype. Hence the two muscarinic pathways use different receptors and different guanine nucleotide binding proteins to produce different actions on channels.

Full text

PDF
9544

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akiba I., Kubo T., Maeda A., Bujo H., Nakai J., Mishina M., Numa S. Primary structure of porcine muscarinic acetylcholine receptor III and antagonist binding studies. FEBS Lett. 1988 Aug 1;235(1-2):257–261. doi: 10.1016/0014-5793(88)81274-2. [DOI] [PubMed] [Google Scholar]
  3. Anwar-ul S., Gilani H., Cobbin L. B. The cardio-selectivity of himbacine: a muscarine receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jan;332(1):16–20. doi: 10.1007/BF00633191. [DOI] [PubMed] [Google Scholar]
  4. Barlow R. B., Berry K. J., Glenton P. A., Nilolaou N. M., Soh K. S. A comparison of affinity constants for muscarine-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29 degrees C and in ileum at 29 degrees C and 37 degrees C. Br J Pharmacol. 1976 Dec;58(4):613–620. doi: 10.1111/j.1476-5381.1976.tb08631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beech D. J., Bernheim L., Hille B. Pertussis toxin and voltage dependence distinguish multiple pathways modulating calcium channels of rat sympathetic neurons. Neuron. 1992 Jan;8(1):97–106. doi: 10.1016/0896-6273(92)90111-p. [DOI] [PubMed] [Google Scholar]
  6. Beech D. J., Bernheim L., Mathie A., Hille B. Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):652–656. doi: 10.1073/pnas.88.2.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bernheim L., Beech D. J., Hille B. A diffusible second messenger mediates one of the pathways coupling receptors to calcium channels in rat sympathetic neurons. Neuron. 1991 Jun;6(6):859–867. doi: 10.1016/0896-6273(91)90226-p. [DOI] [PubMed] [Google Scholar]
  8. Bley K. R., Tsien R. W. Inhibition of Ca2+ and K+ channels in sympathetic neurons by neuropeptides and other ganglionic transmitters. Neuron. 1990 Mar;4(3):379–391. doi: 10.1016/0896-6273(90)90050-p. [DOI] [PubMed] [Google Scholar]
  9. Bonner T. I., Buckley N. J., Young A. C., Brann M. R. Identification of a family of muscarinic acetylcholine receptor genes. Science. 1987 Jul 31;237(4814):527–532. doi: 10.1126/science.3037705. [DOI] [PubMed] [Google Scholar]
  10. Bonner T. I., Young A. C., Brann M. R., Buckley N. J. Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron. 1988 Jul;1(5):403–410. doi: 10.1016/0896-6273(88)90190-0. [DOI] [PubMed] [Google Scholar]
  11. Brown D. A., Adams P. R. Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature. 1980 Feb 14;283(5748):673–676. doi: 10.1038/283673a0. [DOI] [PubMed] [Google Scholar]
  12. Brown D. A., Marrion N. V., Smart T. G. On the transduction mechanism for muscarine-induced inhibition of M-current in cultured rat sympathetic neurones. J Physiol. 1989 Jun;413:469–488. doi: 10.1113/jphysiol.1989.sp017664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brown D. M-currents: an update. Trends Neurosci. 1988 Jul;11(7):294–299. doi: 10.1016/0166-2236(88)90089-6. [DOI] [PubMed] [Google Scholar]
  14. Buckley N. J., Bonner T. I., Buckley C. M., Brann M. R. Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol. 1989 Apr;35(4):469–476. [PubMed] [Google Scholar]
  15. Caulfield M. P., Brown D. A. Pharmacology of the putative M4 muscarinic receptor mediating Ca-current inhibition in neuroblastoma x glioma hybrid (NG 108-15) cells. Br J Pharmacol. 1991 Sep;104(1):39–44. doi: 10.1111/j.1476-5381.1991.tb12381.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Constanti A., Brown D. A. M-Currents in voltage-clamped mammalian sympathetic neurones. Neurosci Lett. 1981 Jul 17;24(3):289–294. doi: 10.1016/0304-3940(81)90173-7. [DOI] [PubMed] [Google Scholar]
  17. Dörje F., Levey A. I., Brann M. R. Immunological detection of muscarinic receptor subtype proteins (m1-m5) in rabbit peripheral tissues. Mol Pharmacol. 1991 Oct;40(4):459–462. [PubMed] [Google Scholar]
  18. Dörje F., Wess J., Lambrecht G., Tacke R., Mutschler E., Brann M. R. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther. 1991 Feb;256(2):727–733. [PubMed] [Google Scholar]
  19. Eltze M. Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol. 1988 Jul 7;151(2):205–221. doi: 10.1016/0014-2999(88)90801-1. [DOI] [PubMed] [Google Scholar]
  20. Fukuda K., Higashida H., Kubo T., Maeda A., Akiba I., Bujo H., Mishina M., Numa S. Selective coupling with K+ currents of muscarinic acetylcholine receptor subtypes in NG108-15 cells. Nature. 1988 Sep 22;335(6188):355–358. doi: 10.1038/335355a0. [DOI] [PubMed] [Google Scholar]
  21. Fukuda K., Kubo T., Akiba I., Maeda A., Mishina M., Numa S. Molecular distinction between muscarinic acetylcholine receptor subtypes. Nature. 1987 Jun 18;327(6123):623–625. doi: 10.1038/327623a0. [DOI] [PubMed] [Google Scholar]
  22. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  23. Hammer R., Berrie C. P., Birdsall N. J., Burgen A. S., Hulme E. C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature. 1980 Jan 3;283(5742):90–92. doi: 10.1038/283090a0. [DOI] [PubMed] [Google Scholar]
  24. Higashida H., Hashii M., Fukuda K., Caulfield M. P., Numa S., Brown D. A. Selective coupling of different muscarinic acetylcholine receptors to neuronal calcium currents in DNA-transfected cells. Proc Biol Sci. 1990 Oct 22;242(1303):68–74. doi: 10.1098/rspb.1990.0105. [DOI] [PubMed] [Google Scholar]
  25. Hirning L. D., Fox A. P., McCleskey E. W., Olivera B. M., Thayer S. A., Miller R. J., Tsien R. W. Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science. 1988 Jan 1;239(4835):57–61. doi: 10.1126/science.2447647. [DOI] [PubMed] [Google Scholar]
  26. Hulme E. C., Birdsall N. J., Buckley N. J. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol. 1990;30:633–673. doi: 10.1146/annurev.pa.30.040190.003221. [DOI] [PubMed] [Google Scholar]
  27. Jenkinson D. H. How we describe competitive antagonists: three questions of usage. Trends Pharmacol Sci. 1991 Feb;12(2):53–54. doi: 10.1016/0165-6147(91)90497-g. [DOI] [PubMed] [Google Scholar]
  28. Jones S. W. Time course of receptor-channel coupling in frog sympathetic neurons. Biophys J. 1991 Aug;60(2):502–507. doi: 10.1016/S0006-3495(91)82077-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kirkwood A., Simmons M. A., Mather R. J., Lisman J. Muscarinic suppression of the M-current is mediated by a rise in internal Ca2+ concentration. Neuron. 1991 Jun;6(6):1009–1014. doi: 10.1016/0896-6273(91)90240-z. [DOI] [PubMed] [Google Scholar]
  30. Kubo T., Fukuda K., Mikami A., Maeda A., Takahashi H., Mishina M., Haga T., Haga K., Ichiyama A., Kangawa K. Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature. 1986 Oct 2;323(6087):411–416. doi: 10.1038/323411a0. [DOI] [PubMed] [Google Scholar]
  31. Kubo T., Maeda A., Sugimoto K., Akiba I., Mikami A., Takahashi H., Haga T., Haga K., Ichiyama A., Kangawa K. Primary structure of porcine cardiac muscarinic acetylcholine receptor deduced from the cDNA sequence. FEBS Lett. 1986 Dec 15;209(2):367–372. doi: 10.1016/0014-5793(86)81144-9. [DOI] [PubMed] [Google Scholar]
  32. Langer S. Z. Presynaptic regulation of the release of catecholamines. Pharmacol Rev. 1980 Dec;32(4):337–362. [PubMed] [Google Scholar]
  33. Lazareno S., Buckley N. J., Roberts F. F. Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. Mol Pharmacol. 1990 Dec;38(6):805–815. [PubMed] [Google Scholar]
  34. Marrion N. V., Smart T. G., Marsh S. J., Brown D. A. Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype. Br J Pharmacol. 1989 Oct;98(2):557–573. doi: 10.1111/j.1476-5381.1989.tb12630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mathie A., Bernheim L., Hille B. Inhibition of N- and L-type calcium channels by muscarinic receptor activation in rat sympathetic neurons. Neuron. 1992 May;8(5):907–914. doi: 10.1016/0896-6273(92)90205-r. [DOI] [PubMed] [Google Scholar]
  36. Murphy T. H., Worley P. F., Baraban J. M. L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron. 1991 Oct;7(4):625–635. doi: 10.1016/0896-6273(91)90375-a. [DOI] [PubMed] [Google Scholar]
  37. Peralta E. G., Ashkenazi A., Winslow J. W., Ramachandran J., Capon D. J. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature. 1988 Aug 4;334(6181):434–437. doi: 10.1038/334434a0. [DOI] [PubMed] [Google Scholar]
  38. Pfaffinger P. Muscarine and t-LHRH suppress M-current by activating an IAP-insensitive G-protein. J Neurosci. 1988 Sep;8(9):3343–3353. doi: 10.1523/JNEUROSCI.08-09-03343.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Plummer M. R., Logothetis D. E., Hess P. Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron. 1989 May;2(5):1453–1463. doi: 10.1016/0896-6273(89)90191-8. [DOI] [PubMed] [Google Scholar]
  40. Plummer M. R., Rittenhouse A., Kanevsky M., Hess P. Neurotransmitter modulation of calcium channels in rat sympathetic neurons. J Neurosci. 1991 Aug;11(8):2339–2348. doi: 10.1523/JNEUROSCI.11-08-02339.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Regan L. J., Sah D. W., Bean B. P. Ca2+ channels in rat central and peripheral neurons: high-threshold current resistant to dihydropyridine blockers and omega-conotoxin. Neuron. 1991 Feb;6(2):269–280. doi: 10.1016/0896-6273(91)90362-4. [DOI] [PubMed] [Google Scholar]
  42. Robbins J., Caulfield M. P., Higashida H., Brown D. A. Genotypic m3-Muscarinic Receptors Preferentially Inhibit M-currents in DNA-transfected NG108-15 Neuroblastoma x Glioma Hybrid Cells. Eur J Neurosci. 1991;3(8):820–824. doi: 10.1111/j.1460-9568.1991.tb01678.x. [DOI] [PubMed] [Google Scholar]
  43. Wanke E., Ferroni A., Malgaroli A., Ambrosini A., Pozzan T., Meldolesi J. Activation of a muscarinic receptor selectively inhibits a rapidly inactivated Ca2+ current in rat sympathetic neurons. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4313–4317. doi: 10.1073/pnas.84.12.4313. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES