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.

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes

Subjects

Abstract

Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways1. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel2,3, is indispensable for taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas their recognition of sour and salty tastes remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells by taste stimuli. Thus, CALHM1 is a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: CALHM1 is selectively expressed in type II taste bud cells.
Figure 2: CALHM1 is essential for sweet, bitter and umami taste perception.
Figure 3: CALHM1 mediates ATP release.
Figure 4: CALHM1 is required for taste-evoked ATP release from taste cells.

References

  1. Chaudhari, N. & Roper, S. D. The cell biology of taste. J. Cell Biol. 190, 285–296 (2010)

    CAS  Article  Google Scholar 

  2. Ma, Z. et al. Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proc. Natl Acad. Sci. USA 109, E1963–E1971 (2012)

    CAS  Article  Google Scholar 

  3. Siebert, A. P. et al. Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins and innexins. J. Biol. Chem. 288, 6140–6153 (2013)

    CAS  Article  Google Scholar 

  4. Chandrashekar, J., Hoon, M. A., Ryba, N. J. & Zuker, C. S. The receptors and cells for mammalian taste. Nature 444, 288–294 (2006)

    ADS  CAS  Article  Google Scholar 

  5. Finger, T. E. et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310, 1495–1499 (2005)

    ADS  CAS  Article  Google Scholar 

  6. Dreses-Werringloer, U. et al. A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβ levels, and Alzheimer’s disease risk. Cell 133, 1149–1161 (2008)

    CAS  Article  Google Scholar 

  7. Koppel, J. et al. CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer’s disease. Mol. Med. 17, 974–979 (2011)

    CAS  Article  Google Scholar 

  8. Lambert, J. C. et al. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer’s disease: a meta-analysis study. J. Alzheimers Dis. 22, 247–255 (2010)

    CAS  Article  Google Scholar 

  9. Moyer, B. D. et al. Expression of genes encoding multi-transmembrane proteins in specific primate taste cell populations. PLoS ONE 4, e7682 (2009)

    ADS  Article  Google Scholar 

  10. Matsumoto, I., Ohmoto, M., Narukawa, M., Yoshihara, Y. & Abe, K. Skn-1a (Pou2f3) specifies taste receptor cell lineage. Nature Neurosci. 14, 685–687 (2011)

    CAS  Article  Google Scholar 

  11. Zhang, Y. et al. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112, 293–301 (2003)

    CAS  Article  Google Scholar 

  12. Huang, Y. J. et al. The role of pannexin 1 hemichannels in ATP release and cell-cell communication in mouse taste buds. Proc. Natl Acad. Sci. USA 104, 6436–6441 (2007)

    ADS  CAS  Article  Google Scholar 

  13. Romanov, R. A. et al. Afferent neurotransmission mediated by hemichannels in mammalian taste cells. EMBO J. 26, 657–667 (2007)

    CAS  Article  Google Scholar 

  14. Vandenbeuch, A., Zorec, R. & Kinnamon, S. C. Capacitance measurements of regulated exocytosis in mouse taste cells. J. Neurosci. 30, 14695–14701 (2010)

    CAS  Article  Google Scholar 

  15. Romanov, R. A. et al. Dispensable ATP permeability of pannexin 1 channels in a heterologous system and in mammalian taste cells. J. Cell Sci. 125, 5514–5523 (2012)

    CAS  Article  Google Scholar 

  16. Sabirov, R. Z. & Okada, Y. ATP release via anion channels. Purinergic Signal. 1, 311–328 (2005)

    CAS  Article  Google Scholar 

  17. Silverman, W., Locovei, S. & Dahl, G. Probenecid, a gout remedy, inhibits pannexin 1 channels. Am. J. Physiol. Cell Physiol. 295, C761–C767 (2008)

    CAS  Article  Google Scholar 

  18. Romanov, R. A. & Kolesnikov, S. S. Electrophysiologically identified subpopulations of taste bud cells. Neurosci. Lett. 395, 249–254 (2006)

    CAS  Article  Google Scholar 

  19. Burnstock, G. & Kennedy, C. P2X receptors in health and disease. Adv. Pharmacol. 61, 333–372 (2011)

    CAS  Article  Google Scholar 

  20. Edwards, F. A., Gibb, A. J. & Colquhoun, D. ATP receptor-mediated synaptic currents in the central nervous system. Nature 359, 144–147 (1992)

    ADS  CAS  Article  Google Scholar 

  21. Evans, R. J., Derkach, V. & Surprenant, A. ATP mediates fast synaptic transmission in mammalian neurons. Nature 357, 503–505 (1992)

    ADS  CAS  Article  Google Scholar 

  22. Cotrina, M. L., Lin, J. H., Lopez-Garcia, J. C., Naus, C. C. & Nedergaard, M. ATP-mediated glia signaling. J. Neurosci. 20, 2835–2844 (2000)

    CAS  Article  Google Scholar 

  23. Cotrina, M. L., Lin, J. H. & Nedergaard, M. Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J. Neurosci. 18, 8794–8804 (1998)

    CAS  Article  Google Scholar 

  24. Burnstock, G. Dual control of local blood flow by purines. Ann. NY Acad. Sci. 603, 31–44 (1990)

    ADS  CAS  Article  Google Scholar 

  25. Chizh, B. A. & Illes, P. P2X receptors and nociception. Pharmacol. Rev. 53, 553–568 (2001)

    CAS  PubMed  Google Scholar 

  26. Cockayne, D. A. et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407, 1011–1015 (2000)

    ADS  CAS  Article  Google Scholar 

  27. Wynn, G., Rong, W., Xiang, Z. & Burnstock, G. Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum. Gastroenterology 125, 1398–1409 (2003)

    CAS  Article  Google Scholar 

  28. Ohmoto, M., Matsumoto, I., Misaka, T. & Abe, K. Taste receptor cells express voltage-dependent potassium channels in a cell age-specific manner. Chem. Senses 31, 739–746 (2006)

    CAS  Article  Google Scholar 

  29. Dvoryanchikov, G., Sinclair, M. S., Perea-Martinez, I., Wang, T. & Chaudhari, N. Inward rectifier channel, ROMK, is localized to the apical tips of glial-like cells in mouse taste buds. J. Comp. Neurol. 517, 1–14 (2009)

    CAS  Article  Google Scholar 

  30. Sinclair, M. S. et al. Oxytocin signaling in mouse taste buds. PLoS ONE 5, e11980 (2010)

    ADS  Article  Google Scholar 

  31. Tordoff, M. G. & Bachmanov, A. A. Mouse taste preference tests: why only two bottles? Chem. Senses 28, 315–324 (2003)

    Article  Google Scholar 

  32. Damak, S. et al. Trpm5 null mice respond to bitter, sweet, and umami compounds. Chem. Senses 31, 253–264 (2006)

    MathSciNet  CAS  Article  Google Scholar 

  33. Eddy, M. C. et al. Double P2X2/P2X3 purinergic receptor knockout mice do not taste NaCl or the artificial sweetener SC45647. Chem. Senses 34, 789–797 (2009)

    CAS  Article  Google Scholar 

  34. Glendinning, J. I., Gresack, J. & Spector, A. C. A high-throughput screening procedure for identifying mice with aberrant taste and oromotor function. Chem. Senses 27, 461–474 (2002)

    Article  Google Scholar 

  35. Hallock, R. M., Tatangelo, M., Barrows, J. & Finger, T. E. Residual chemosensory capabilities in double P2X2/P2X3 purinergic receptor null mice: intraoral or postingestive detection? Chem. Senses 34, 799–808 (2009)

    CAS  Article  Google Scholar 

  36. Spector, A. C., Andrews-Labenski, J. & Letterio, F. C. A new gustometer for psychophysical taste testing in the rat. Physiol. Behav. 47, 795–803 (1990)

    CAS  Article  Google Scholar 

  37. Hellekant, G. & Roberts, T. W. in Experimental Cell Biology of Taste and Olfaction: Current Techniques and Protocols (eds Spielman, A. I. & Brand, J. G.) 277–290 (CRC, 1995)

    Google Scholar 

  38. Li, A., Leung, C. T., Peterson-Yantorno, K., Mitchell, C. H. & Civan, M. M. Pathways for ATP release by bovine ciliary epithelial cells, the initial step in purinergic regulation of aqueous humor inflow. Am. J. Physiol. Cell Physiol. 299, C1308–C1317 (2010)

    CAS  Article  Google Scholar 

  39. Clapp, T. R., Medler, K. F., Damak, S., Margolskee, R. F. & Kinnamon, S. C. Mouse taste cells with G protein-coupled taste receptors lack voltage-gated calcium channels and SNAP-25. BMC Biol. 4, 7 (2006)

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a KeySpan award to P.M., several US NIH grants (GM56328, MH059937, NS072775 to J.K.F.; DC10393 to M.G.T.; EY13624 to M.M.C.; R03DC011143 to I.M.; Core Grant P30 EY001583 to the University of Pennsylvania; Core Grant P30DC011735 to the Monell Chemical Senses Center) and the University of Minnesota’s Undergraduate Research Opportunities Program to S.L. and M.A. A.T. and M.O. are JSPS Fellows. We thank R. F. Margolskee for the TRPM5–GFP mice and Y. Ninomiya for comments on the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

A.T., V.V., A.L., Z.M., M.O., I.M., H.Z., L.A., S.L., M.A., G.H., G.D. and N.C. designed and performed experiments. P.M. and V.V. generated the Calhm1 knockout mice. J.K. and P.D. designed experiments. M.G.T., M.M.C., P.M. and J.K.F. designed experiments and helped with data interpretation. A.T., J.K.F. and P.M. wrote the manuscript.

Corresponding authors

Correspondence to Philippe Marambaud or J. Kevin Foskett.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11, Supplementary Tables 1-4, a Supplementary Discussion and additional references. (PDF 2538 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Taruno, A., Vingtdeux, V., Ohmoto, M. et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 495, 223–226 (2013). https://doi.org/10.1038/nature11906

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11906

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