iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1038/nature07579
Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80 | Nature
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80

Nature volume 457, pages 741–744 (2009)Cite this article

Abstract

Several neurotransmitters act through G-protein-coupled receptors to evoke a ‘slow’ excitation of neurons1,2. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K+ currents and/or activating a non-selective cation channel3,4,5,6,7,8,9. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: NALCN is required for ISP.
Figure 2: Characterization of the I SP in hippocampal neurons.
Figure 3: I SP is G-protein-independent but requires SFKs.
Figure 4: I SP reconstituted in HEK293T cells.

Similar content being viewed by others

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

The sequence of mUNC-80 is deposited in GenBank under accession number FJ210934.

References

  1. Kandel, E. R., Schwartz, J. H. & Jessell, T. M. Principles of Neural Science 229–252 (McGraw-Hill, 2000)

    Google Scholar 

  2. Hille, B. Ion Channels of Excitable Membranes 201–236 (Sinauer, 2001)

    Google Scholar 

  3. Kuba, K. & Koketsu, K. Synaptic events in sympathetic ganglia. Prog. Neurobiol. 11, 77–169 (1978)

    Article  CAS  Google Scholar 

  4. Jan, Y., Jan, L. & Kuffler, S. Further evidence for peptidergic transmission in smypathetic ganglia. Proc. Natl Acad. Sci. USA 77, 5008–5012 (1980)

    Article  ADS  CAS  Google Scholar 

  5. Kuffler, S. & Sejnowski, T. Muscarinic and peptidergic excitation of bull-frog sympathetic neurons. J. Physiol. (Lond.) 341, 257–278 (1983)

    Article  CAS  Google Scholar 

  6. Stanfield, P. R., Nakajima, Y. & Yamaguchi, K. Substance P raises neuronal membrane excitability by reducing inward rectification. Nature 315, 498–501 (1985)

    Article  ADS  CAS  Google Scholar 

  7. Shen, K. Z. & North, R. A. Muscarine increases cation conductance and decreases potassium conductance in rat locus coeruleus neurones. J. Physiol. (Lond.) 455, 471–485 (1992)

    Article  CAS  Google Scholar 

  8. Shen, K. Z. & Surprenant, A. Common ionic mechanisms of excitation by substance P and other transmitters in guinea-pig submucosal neurones. J. Physiol. (Lond.) 462, 483–501 (1993)

    Article  CAS  Google Scholar 

  9. Farkas, R. H., Chien, P. Y., Nakajima, S. & Nakajima, Y. Properties of a slow nonselective cation conductance modulated by neurotensin and other neurotransmitters in midbrain dopaminergic neurons. J. Neurophysiol. 76, 1968–1981 (1996)

    Article  CAS  Google Scholar 

  10. Lu, B. et al. The neuronal NALCN channel contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129, 371–383 (2007)

    Article  CAS  Google Scholar 

  11. Shen, K. Z. & North, R. A. Substance P opens cation channels and closes potassium channels in rat locus coeruleus neurons. Neuroscience 50, 345–353 (1992)

    Article  CAS  Google Scholar 

  12. Aosaki, T. & Kawaguchi, Y. Actions of substance P on rat neostriatal neurons in vitro . J. Neurosci. 16, 5141–5153 (1996)

    Article  CAS  Google Scholar 

  13. Inoue, K., Nakazawa, K., Inoue, K. & Fujimori, K. Nonselective cation channels coupled with tachykinin receptors in rat sensory neurons. J. Neurophysiol. 73, 736–742 (1995)

    Article  CAS  Google Scholar 

  14. Pena, F. & Ramirez, J. M. Substance P-mediated modulation of pacemaker properties in the mammalian respiratory network. J. Neurosci. 24, 7549–7556 (2004)

    Article  CAS  Google Scholar 

  15. Jones, S. W. Muscarinic and peptidergic excitation of bull-frog sympathetic neurones. J. Physiol. (Lond.) 366, 63–87 (1985)

    Article  ADS  CAS  Google Scholar 

  16. Otsuka, M. & Yoshioka, K. Neurotransmitter functions of mammalian tachykinins. Physiol. Rev. 73, 229–308 (1993)

    Article  CAS  Google Scholar 

  17. Lefkowitz, R. J. & Shenoy, S. K. Transduction of receptor signals by β-arrestins. Science 308, 512–517 (2005)

    Article  ADS  CAS  Google Scholar 

  18. DeFea, K. A. et al. The proliferative and antiapoptotic effects of substance P are facilitated by formation of β-arrestin-dependent scaffolding complex. Proc. Natl Acad. Sci. USA 97, 11086–11091 (2000)

    Article  ADS  CAS  Google Scholar 

  19. Heuss, C., Scanziani, M., Gahwiler, B. H. & Gerber, U. G-protein-indenpendent signaling mediated by metabotropic glutamate receptors. Nature Neurosci. 2, 1070–1077 (1999)

    Article  CAS  Google Scholar 

  20. Davis, M. J. et al. Regulation of ion channels by protein tyrosine phosphorylation. Am. J. Physiol. Heart Circ. Physiol. 281, H1835–H1862 (2001)

    Article  CAS  Google Scholar 

  21. Salters, M. W. & Kalia, L. V. Src kinases: a hub for NMDA receptor regulation. Nature Rev. Neurosci. 5, 317–328 (2004)

    Article  Google Scholar 

  22. Heuss, C. & Gerber, U. G-protein-independent signaling by G-protein-coupled receptors. Trends Neurosci. 23, 469–475 (2000)

    Article  CAS  Google Scholar 

  23. Montell, C., Birnbaumer, L. & Flockerzi, V. The TRP channels, a remarkably functional family. Cell 108, 595–598 (2002)

    Article  CAS  Google Scholar 

  24. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003)

    Article  ADS  CAS  Google Scholar 

  25. Oh, E. J., Gover, T. D., Cordoba-Rodriguez, R. & Weinreich, D. Substance P evokes cation currents through TRP channels in HEK293 cells. J. Neurophysiol. 90, 2069–2073 (2003)

    Article  CAS  Google Scholar 

  26. Bley, K. R. & Tsien, R. W. Inhibition of Ca2+ and K+ channels in sympathetic neurons by neuropeptides and other ganglionic transmitters. Neuron 4, 379–391 (1990)

    Article  CAS  Google Scholar 

  27. Jospin, M. et al. UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. Curr. Biol. 17, 1595–1600 (2007)

    Article  CAS  Google Scholar 

  28. Yeh, E. et al. A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans . PLoS Biol. 6, e55 (2008)

    Article  Google Scholar 

  29. Humphrey, J. A. et al. A putative cation channel and its novel regulator: cross-species conservation of effects on general anesthesia. Curr. Biol. 17, 624–629 (2007)

    Article  CAS  Google Scholar 

  30. Liu, J., Xia, J., Cho, K. H., Clapham, D. E. & Ren, D. Catsper β: a novel transmembrane protein in the catsper channel complex. J. Biol. Chem. 282, 18945–18952 (2007)

    Article  CAS  Google Scholar 

  31. Masuko, S., Nakajima, S. & Nakajima, Y. Dissociated high-purity dopaminergic neuron cultures from the substantia nigra and the ventral tegmental area of the postnatal rat. Neuroscience 49, 347–364 (1992)

    Article  CAS  Google Scholar 

  32. Rayport, S. et al. Identified postnatal mesolimbic dopamine neurons in culture: morphology and electrophysiology. J. Neurosci. 12, 4264–4280 (1992)

    Article  CAS  Google Scholar 

  33. Grace, A. A. & Onn, S.-P. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J. Neurosci. 9, 3463–3481 (1989)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Clapham, C. Deutsch, I. Medina, B. Novarro, M. Schmidt and H. Xu for critically reading earlier versions of the manuscript, J. Xia for help with experiments, H. Yu and L. Yue for cDNA constructs, and Sanofi-Aventis for the gift of SR48692. This work was supported, in part, by funding from American Heart Association, the NIH and the University of Pennsylvania Research Foundation.

Author Contributions B.L. did recordings from neurons (Figs 1–3 and Supplementary Fig. 2) and all the HEK293T cells (Fig. 4 and Supplementary Figs 1 and 7–10). Y.S. contributed to neuronal recordings (Figs 1 and 2 and Supplementary Figs 3 and 4). S.D. contributed to work in Fig. 2. H.W., Y.W. and J.L. did the protein work (Fig. 4 and Supplementary Fig. 6). D.R. started the project, designed experiments and developed the cDNA constructs. B.L. and D.R. wrote the paper.

Author information

Author notes

  1. Yanhua Su

    Present address: Present address: State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, Nanjing 210008, China.,

  2. Boxun Lu and Yanhua Su: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, University of Pennsylvania, 415 S. University Avenue, Philadelphia, Pennsylvania 19104, USA,

    Boxun Lu, Yanhua Su, Sudipto Das, Haikun Wang, Yan Wang, Jin Liu & Dejian Ren

Authors
  1. Boxun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanhua Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sudipto Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haikun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dejian Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dejian Ren.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-10 with Legends (PDF 461 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, B., Su, Y., Das, S. et al. Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457, 741–744 (2009). https://doi.org/10.1038/nature07579

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07579

This article is cited by

Search

Advanced 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