Direct modulation of synaptic vesicle priming by GABAB receptor activation at a glutamatergic synapse

Abstract

Second messenger cascades involving G proteins1,2 and calcium3 are known to modulate neurotransmitter release4,5. A prominent effect of such a cascade is the downmodulation of presynaptic calcium influx6,7, which markedly reduces evoked neurotransmitter release5,7,8. Here we show that G-protein-mediated signalling, such as through GABA (γ-amino butyric acid) subtype B (GABAB) receptors, retards the recruitment of synaptic vesicles during sustained activity and after short-term depression. This retardation occurs through a lowering of cyclic AMP, which blocks the stimulatory effect of increased calcium concentration on vesicle recruitment. In this signalling pathway, cAMP (functioning through the cAMP-dependent guanine nucleotide exchange factor) and calcium/calmodulin cooperate to enhance vesicle priming. The differential modulation of the two forms of synaptic plasticity, presynaptic inhibition and calcium-dependent recovery from synaptic depression, is expected to have interesting consequences for the dynamic behaviour of neural networks.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Effects of baclofen on synaptic transmission at the calyx of Held.
Figure 2: Inhibitory effect of baclofen on vesicle recruitment.
Figure 3: Supplementation of cAMP prevents the inhibitory effect of GDP-βS.

References

  1. 1

    Simon, M. I., Strathmann, M. P. & Gautam, N. Diversity of G proteins in signal transduction. Science 252, 802–808 (1991)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Gilman, A. G. G proteins and regulation of adenylyl cyclase. Biosci. Rep. 15, 65–97 (1995)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Zucker, R. S. & Regehr, W. G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Nicoll, R. A., Malenka, R. C. & Kauer, J. A. Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiol. Rev. 70, 513–565 (1990)

    CAS  Article  Google Scholar 

  5. 5

    Wu, L. G. & Saggau, P. Presynaptic inhibition of elicited neurotransmitter release. Trends Neurosci. 20, 204–212 (1997)

    CAS  Article  Google Scholar 

  6. 6

    Kajikawa, Y., Saitoh, N. & Takahashi, T. GTP-binding protein βγ subunits mediate presynaptic calcium current inhibition by GABAB receptor. Proc. Natl Acad. Sci. USA 98, 8054–8058 (2001)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Dittman, J. S. & Regehr, W. G. Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. J. Neurosci. 16, 1623–1633 (1996)

    CAS  Article  Google Scholar 

  8. 8

    Takahashi, T., Kajikawa, Y. & Tsujimoto, T. G-protein-coupled modulation of presynaptic calcium currents and transmitter release by a GABAB receptor. J. Neurosci. 18, 3138–3146 (1998)

    CAS  Article  Google Scholar 

  9. 9

    Forsythe, I. D. Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. J. Physiol. (Lond.) 479, 381–387 (1994)

    Article  Google Scholar 

  10. 10

    Borst, J. G. G., Helmchen, F. & Sakmann, B. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. (Lond.) 489, 825–840 (1995)

    CAS  Article  Google Scholar 

  11. 11

    Barnes-Davies, M. B. & Forsythe, I. D. Pre- and postsynaptic glutamate receptors at a giant synapse in rat auditory brainstem slices. J. Physiol. (Lond.) 488, 387–406 (1995)

    CAS  Article  Google Scholar 

  12. 12

    Isaacson, J. S. GABAB receptor-mediated modulation of presynaptic currents and excitatory transmission at a fast central synapse. J. Neurophysiol. 80, 1571–1576 (1998)

    CAS  Article  Google Scholar 

  13. 13

    Takahashi, T., Hori, T., Kajikawa, Y. & Tsujimoto, T. The role of GTP-binding protein activity in fast central synaptic transmission. Science 289, 460–463 (2000)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Hess, S. D., Doroshenko, P. A. & Augustine, G. J. A functional role for GTP-binding proteins in synaptic vesicle cycling. Science 259, 1169–1172 (1993)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Dittman, J. S. & Regehr, W. G. Calcium dependence and recovery kinetics of presynaptic depression at the climbing fiber to Purkinje cell synapse. J. Neurosci. 18, 6147–6162 (1998)

    CAS  Article  Google Scholar 

  16. 16

    Stevens, C. F. & Wesseling, J. F. Activity-dependent modulation of the rate at which synaptic vesicles become available to undergo exocytosis. Neuron 21, 415–424 (1998)

    CAS  Article  Google Scholar 

  17. 17

    Wang, L. Y. & Kaczmarek, L. K. High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384–388 (1998)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Sakaba, T. & Neher, E. Calmodulin mediates rapid recruitment of fast-releasing synaptic vesicles at a calyx-type synapse. Neuron 32, 1119–1131 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Cuttle, M. F., Tsujimoto, T., Forsythe, I. D. & Takahashi, T. Facilitation of the presynaptic calcium current at an auditory synapse in rat brainstem. J. Physiol. (Lond.) 512, 723–729 (1998)

    CAS  Article  Google Scholar 

  20. 20

    Seifert, R. & Wenzel-Seifert, K. Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 366, 381–416 (2002)

    CAS  Article  Google Scholar 

  21. 21

    Sakaba, T. & Neher, E. Preferential potentiation of fast-releasing synaptic vesicles by cAMP at the calyx of Held. Proc. Natl Acad. Sci. USA 98, 331–336 (2001)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Sakaba, T. & Neher, E. Involvement of actin polymerization in vesicle recruitment at the calyx of Held synapse. J. Neurosci. 23, 837–846 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Enserink, J. M. et al. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nature Cell Biol. 4, 901–906 (2002)

    CAS  Article  Google Scholar 

  24. 24

    Ozaki, N. et al. cAMP-GEF II is a direct target of cAMP in regulated exocytosis. Nature Cell Biol. 2, 805–811 (2000)

    CAS  Article  Google Scholar 

  25. 25

    Betz, A. et al. Functional interaction of the active zone protein Munc13-1 and Rim1 in synaptic vesicle priming. Neuron 30, 183–196 (2001)

    CAS  Article  Google Scholar 

  26. 26

    Xu, X. Z. S. et al. Retinal targets for calmodulin include proteins implicated in synaptic transmission. J. Biol. Chem. 273, 31297–31307 (1998)

    CAS  Article  Google Scholar 

  27. 27

    Eliasson, L. et al. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. J. Gen. Physiol. 121, 181–197 (2003)

    CAS  Article  Google Scholar 

  28. 28

    Silinsky, E. M. On the mechanism by which adenosine receptor activation inhibits the release of acetylcholine from motor-nerve endings. J. Physiol. (Lond.) 346, 243–256 (1984)

    CAS  Article  Google Scholar 

  29. 29

    Dale, N. & Kandel, E. R. Facilitatory and inhibitory transmitters modulate spontaneous transmitter release at cultured Aplysia sensorimotor synapses. J. Physiol. (Lond.) 421, 203–222 (1990)

    CAS  Article  Google Scholar 

  30. 30

    Scanziani, M., Capogna, M., Gahwiler, B. H. & Thompson, S. M. Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocamus. Neuron 9, 919–927 (1992)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank N. Brose, F. Felmy, C. Rosenmund, F. Sachs, R. Schneggenburger, G. Schultz and M. Wölfel for critical comments on the manuscript. This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (DFG Research Center on Molecular Physiology of the Brain).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Erwin Neher.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sakaba, T., Neher, E. Direct modulation of synaptic vesicle priming by GABAB receptor activation at a glutamatergic synapse. Nature 424, 775–778 (2003). https://doi.org/10.1038/nature01859

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing