Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1997 Apr 15;500(Pt 2):487–496. doi: 10.1113/jphysiol.1997.sp022035

G-protein-mediated desensitization of metabotropic glutamatergic and muscarinic responses in CA3 cells in rat hippocampus.

N C Guérineau 1, J L Bossu 1, B H Gähwiler 1, U Gerber 1
PMCID: PMC1159398  PMID: 9147332

Abstract

1. Desensitization of a metabotropic response was investigated in CA3 pyramidal neurons in hippocampal slice cultures using the patch-clamp technique. 2. 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), an agonist at metabotropic glutamate receptors (mGluRs), and metacholine (MCh), an agonist at muscarinic receptors, induced a cationic current that appears to be activated through a G-protein-independent transduction process, as previously shown. Prolonged or repetitive bath application of agonists led to rapid desensitization of the cationic current with a time constant of approximately 20 s. 3. Complete recovery from desensitization was observed within 6 min. 4. These responses mediated by mGluRs and muscarinic receptors cross-desensitized. 5. Preventing the activation of G-proteins by loading cells with GDP beta S strongly reduced or suppressed desensitization, and resulted in a sustained inward cationic current. When cells were filled with GTP gamma S to irreversibly activate G-proteins, the desensitization process was enhanced such that a first application of agonist caused a markedly reduced response. 6. These results show that a cationic current induced by metabotropic agonists in hippocampal pyramidal cells undergoes apparent desensitization and suggests that this process occurs through a G-protein-mediated inhibition of the underlying membrane conductance.

Full text

PDF
487

Selected References

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

  1. Alaluf S., Mulvihill E. R., McIlhinney R. A. Rapid agonist mediated phosphorylation of the metabotropic glutamate receptor 1 alpha by protein kinase C in permanently transfected BHK cells. FEBS Lett. 1995 Jul 3;367(3):301–305. doi: 10.1016/0014-5793(95)00575-t. [DOI] [PubMed] [Google Scholar]
  2. Andrade R., Malenka R. C., Nicoll R. A. A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science. 1986 Dec 5;234(4781):1261–1265. doi: 10.1126/science.2430334. [DOI] [PubMed] [Google Scholar]
  3. Bianchi R., Wong R. K. Carbachol-induced synchronized rhythmic bursts in CA3 neurons of guinea pig hippocampus in vitro. J Neurophysiol. 1994 Jul;72(1):131–138. doi: 10.1152/jn.1994.72.1.131. [DOI] [PubMed] [Google Scholar]
  4. Bianchi R., Wong R. K. Excitatory synaptic potentials dependent on metabotropic glutamate receptor activation in guinea-pig hippocampal pyramidal cells. J Physiol. 1995 Sep 15;487(Pt 3):663–676. doi: 10.1113/jphysiol.1995.sp020908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boland L. M., Bean B. P. Modulation of N-type calcium channels in bullfrog sympathetic neurons by luteinizing hormone-releasing hormone: kinetics and voltage dependence. J Neurosci. 1993 Feb;13(2):516–533. doi: 10.1523/JNEUROSCI.13-02-00516.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Canonico P. L., Favit A., Catania M. V., Nicoletti F. Phorbol esters attenuate glutamate-stimulated inositol phospholipid hydrolysis in neuronal cultures. J Neurochem. 1988 Oct;51(4):1049–1053. doi: 10.1111/j.1471-4159.1988.tb03067.x. [DOI] [PubMed] [Google Scholar]
  7. Catania M. V., Aronica E., Sortino M. A., Canonico P. L., Nicoletti F. Desensitization of metabotropic glutamate receptors in neuronal cultures. J Neurochem. 1991 Apr;56(4):1329–1335. doi: 10.1111/j.1471-4159.1991.tb11429.x. [DOI] [PubMed] [Google Scholar]
  8. Charpak S., Gähwiler B. H., Do K. Q., Knöpfel T. Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters. Nature. 1990 Oct 25;347(6295):765–767. doi: 10.1038/347765a0. [DOI] [PubMed] [Google Scholar]
  9. Chavis P., Nooney J. M., Bockaert J., Fagni L., Feltz A., Bossu J. L. Facilitatory coupling between a glutamate metabotropic receptor and dihydropyridine-sensitive calcium channels in cultured cerebellar granule cells. J Neurosci. 1995 Jan;15(1 Pt 1):135–143. doi: 10.1523/JNEUROSCI.15-01-00135.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chavis P., Shinozaki H., Bockaert J., Fagni L. The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells. J Neurosci. 1994 Nov;14(11 Pt 2):7067–7076. doi: 10.1523/JNEUROSCI.14-11-07067.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elhamdani A., Bossu J. L., Feltz A. ATP and G proteins affect the runup of the Ca2+ current in bovine chromaffin cells. Pflugers Arch. 1995 Jul;430(3):410–419. doi: 10.1007/BF00373917. [DOI] [PubMed] [Google Scholar]
  12. Guérineau N. C., Bossu J. L., Gähwiler B. H., Gerber U. Activation of a nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus. J Neurosci. 1995 Jun;15(6):4395–4407. doi: 10.1523/JNEUROSCI.15-06-04395.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guérineau N. C., Gähwiler B. H., Gerber U. Reduction of resting K+ current by metabotropic glutamate and muscarinic receptors in rat CA3 cells: mediation by G-proteins. J Physiol. 1994 Jan 1;474(1):27–33. doi: 10.1113/jphysiol.1994.sp019999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gähwiler B. H. Organotypic monolayer cultures of nervous tissue. J Neurosci Methods. 1981 Dec;4(4):329–342. doi: 10.1016/0165-0270(81)90003-0. [DOI] [PubMed] [Google Scholar]
  15. Hayashi Y., Momiyama A., Takahashi T., Ohishi H., Ogawa-Meguro R., Shigemoto R., Mizuno N., Nakanishi S. Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb. Nature. 1993 Dec 16;366(6456):687–690. doi: 10.1038/366687a0. [DOI] [PubMed] [Google Scholar]
  16. Herrero I., Miras-Portugal M. T., Sánchez-Prieto J. Rapid desensitization of the metabotropic glutamate receptor that facilitates glutamate release in rat cerebrocortical nerve terminals. Eur J Neurosci. 1994 Jan 1;6(1):115–120. doi: 10.1111/j.1460-9568.1994.tb00253.x. [DOI] [PubMed] [Google Scholar]
  17. Houslay M. D. 'Crosstalk': a pivotal role for protein kinase C in modulating relationships between signal transduction pathways. Eur J Biochem. 1991 Jan 1;195(1):9–27. doi: 10.1111/j.1432-1033.1991.tb15671.x. [DOI] [PubMed] [Google Scholar]
  18. Huganir R. L., Greengard P. Regulation of neurotransmitter receptor desensitization by protein phosphorylation. Neuron. 1990 Nov;5(5):555–567. doi: 10.1016/0896-6273(90)90211-w. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. KATZ B., THESLEFF S. A study of the desensitization produced by acetylcholine at the motor end-plate. J Physiol. 1957 Aug 29;138(1):63–80. doi: 10.1113/jphysiol.1957.sp005838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Katada T., Ui M. Direct modification of the membrane adenylate cyclase system by islet-activating protein due to ADP-ribosylation of a membrane protein. Proc Natl Acad Sci U S A. 1982 May;79(10):3129–3133. doi: 10.1073/pnas.79.10.3129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kim D. Mechanism of rapid desensitization of muscarinic K+ current in adult rat and guinea pig atrial cells. Circ Res. 1993 Jul;73(1):89–97. doi: 10.1161/01.res.73.1.89. [DOI] [PubMed] [Google Scholar]
  23. Kurachi Y., Nakajima T., Sugimoto T. Short-term desensitization of muscarinic K+ channel current in isolated atrial myocytes and possible role of GTP-binding proteins. Pflugers Arch. 1987 Oct;410(3):227–233. doi: 10.1007/BF00580270. [DOI] [PubMed] [Google Scholar]
  24. McBain C. J., DiChiara T. J., Kauer J. A. Activation of metabotropic glutamate receptors differentially affects two classes of hippocampal interneurons and potentiates excitatory synaptic transmission. J Neurosci. 1994 Jul;14(7):4433–4445. doi: 10.1523/JNEUROSCI.14-07-04433.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Merlin L. R., Taylor G. W., Wong R. K. Role of metabotropic glutamate receptor subtypes in the patterning of epileptiform activities in vitro. J Neurophysiol. 1995 Aug;74(2):896–900. doi: 10.1152/jn.1995.74.2.896. [DOI] [PubMed] [Google Scholar]
  26. Mubagwa K., Gilbert J. C., Pappano A. J. Differential time course for desensitization to muscarinic effects on K+ and Ca2+ channels. Pflugers Arch. 1994 Oct;428(5-6):542–551. doi: 10.1007/BF00374576. [DOI] [PubMed] [Google Scholar]
  27. Nah S. Y., Attali B., Vogel Z. Heterologous desensitization and reduced G protein ADP-ribosylation following exposure to alpha 2-adrenoceptor and muscarinic receptor agonists. Eur J Pharmacol. 1993 Jan 4;244(1):67–75. doi: 10.1016/0922-4106(93)90060-m. [DOI] [PubMed] [Google Scholar]
  28. Netzer R., Pflimlin P., Trube G. Tonic inhibition of neuronal calcium channels by G proteins removed during whole-cell patch-clamp experiments. Pflugers Arch. 1994 Feb;426(3-4):206–213. doi: 10.1007/BF00374773. [DOI] [PubMed] [Google Scholar]
  29. Pin J. P., Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995 Jan;34(1):1–26. doi: 10.1016/0028-3908(94)00129-g. [DOI] [PubMed] [Google Scholar]
  30. Poncer J. C., Shinozaki H., Miles R. Dual modulation of synaptic inhibition by distinct metabotropic glutamate receptors in the rat hippocampus. J Physiol. 1995 May 15;485(Pt 1):121–134. doi: 10.1113/jphysiol.1995.sp020717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schoepp D. D., Johnson B. G. Selective inhibition of excitatory amino acid-stimulated phosphoinositide hydrolysis in the rat hippocampus by activation of protein kinase C. Biochem Pharmacol. 1988 Nov 15;37(22):4299–4305. doi: 10.1016/0006-2952(88)90610-7. [DOI] [PubMed] [Google Scholar]
  32. Shirasaki T., Harata N., Akaike N. Metabotropic glutamate response in acutely dissociated hippocampal CA1 pyramidal neurones of the rat. J Physiol. 1994 Mar 15;475(3):439–453. doi: 10.1113/jphysiol.1994.sp020084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shui Z., Boyett M. R., Zang W. J., Haga T., Kameyama K. Receptor kinase-dependent desensitization of the muscarinic K+ current in rat atrial cells. J Physiol. 1995 Sep 1;487(Pt 2):359–366. doi: 10.1113/jphysiol.1995.sp020885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Staub C., Vranesic I., Knöpfel T. Responses to Metabotropic Glutamate Receptor Activation in Cerebellar Purkinje Cells: Induction of an Inward Current. Eur J Neurosci. 1992;4(9):832–839. doi: 10.1111/j.1460-9568.1992.tb00193.x. [DOI] [PubMed] [Google Scholar]
  35. Tan Y. P., Marty A. Protein kinase C-mediated desensitization of the muscarinic response in rat lacrimal gland cells. J Physiol. 1991 Feb;433:357–371. doi: 10.1113/jphysiol.1991.sp018430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Thomsen C., Mulvihill E. R., Haldeman B., Pickering D. S., Hampson D. R., Suzdak P. D. A pharmacological characterization of the mGluR1 alpha subtype of the metabotropic glutamate receptor expressed in a cloned baby hamster kidney cell line. Brain Res. 1993 Aug 13;619(1-2):22–28. doi: 10.1016/0006-8993(93)91592-g. [DOI] [PubMed] [Google Scholar]
  37. Turecek R., Vyklický L., Vlachová V., Vyklický L., Jr G-protein modulation of glycine-resistant NMDA receptor desensitization in rat cultured hippocampal neurons. Eur J Neurosci. 1995 Aug 1;7(8):1826–1830. doi: 10.1111/j.1460-9568.1995.tb00702.x. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES