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.

  • Article
  • Published:

Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons

Nature Neuroscience volume 8, pages 1335–1342 (2005)Cite this article

Abstract

Sound localization by auditory brainstem nuclei relies on the detection of microsecond interaural differences in action potentials that encode sound volume and timing. Neurons in these nuclei express high amounts of the Kv3.1 potassium channel, which allows them to fire at high frequencies with short-duration action potentials. Using computational modeling, we show that high amounts of Kv3.1 current decrease the timing accuracy of action potentials but enable neurons to follow high-frequency stimuli. The Kv3.1b channel is regulated by protein kinase C (PKC), which decreases current amplitude. Here we show that in a quiet environment, Kv3.1b is basally phosphorylated in rat brainstem neurons but is rapidly dephosphorylated in response to high-frequency auditory or synaptic stimulation. Dephosphorylation of the channel produced an increase in Kv3.1 current, facilitating high-frequency spiking. Our results indicate that the intrinsic electrical properties of auditory neurons are rapidly modified to adjust to the ambient acoustic environment. *Note: In the version of this article initially published online, some of the authors’ affiliations were incorrectly reported. These affiliations have been corrected for the HTML and print versions of the article. The correct affiliations are Ping Song 1 , Yue Yang 2 , Margaret Barnes-Davies 3,5 , Arin Bhattacharjee 1,5 , Martine Hamann 3 , Ian D Forsythe 4 , Douglas L Oliver 2 & Leonard K Kaczmarek 1

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Increases in Kv3.1 current enhance high-frequency firing but impair timing accuracy.
Figure 2: Kv3.1b channels are basally phosphorylated in auditory neurons but not in transfected CHO cells.
Figure 3: Tonotopic gradient of Kv3.1b phosphorylation in normal and PMA-treated MNTB.
Figure 4: High-frequency electrical stimulation of brainstem slices produces a decrease in Kv3.1b phosphorylation and an increase in Kv3.1b current in MNTB neurons.
Figure 5: Inhibition of phosphatases PP1/PP2A but not PP2B prevents stimulation-induced dephosphorylation of Kv3.1b channels.
Figure 6: Kv3.1b phosphorylation is reduced in vivo after high-frequency binaural auditory stimulation.
Figure 7: Side-to-side comparison of Kv3.1b phosphorylation in rats exposed to monaural acoustic stimulation.

Similar content being viewed by others

References

  1. Perney, T.M., Marshall, J., Martin, K.A., Hockfield, S. & Kaczmarek, L.K. Expression of the mRNAs for the Kv3.1 potassium channel gene in the adult and developing brain. J. Neurophysiol. 68, 756–766 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Lenz, S., Perney, T.M., Qin, Y., Robbins, E. & Chesselet, M.F. GABAergic interneurons of the striatum express the Shaw-like potassium channel Kv3.1. Synapse 18, 55–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Weiser, M. et al. The potassium channel subunit Kv3.1b is localized to somatic and axonal membranes of specific populations of CNS neurons. J. Neurosci. 15, 4298–4314 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brew, H.M. & Forsythe, I.D. Two voltage-dependent K+ conductances with complementary functions in postsynaptic integration at a central auditory synapse. J. Neurosci. 15, 8011–8022 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sekirnjak, C. et al. Subcellular localization of the K+ channel subunit Kv3.1b in selected rat CNS neurons. Brain Res. 766, 173–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Rudy, B. & McBain, C.J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Matsukawa, H., Wolf, A.M., Matsushita, S., Joho, R.H. & Knopfel, T. Motor dysfunction and altered synaptic transmission at the parallel fiber-Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3. J. Neurosci. 23, 7677–7684 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Smith, P.H., Joris, P.X., Carney, L.H. & Yin, T.C. Projections of physiologically characterized globular bushy cell axons from the cochlear nucleus of the cat. J. Comp. Neurol. 304, 387–407 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Wu, S.H. & Kelly, J.B. Response of neurons in the lateral superior olive and medial nucleus of the trapezoid body to repetitive stimulation: intracellular and extracellular recordings from mouse brain slice. Hear. Res. 68, 189–201 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Satzler, K. et al. Three-dimensional reconstruction of a calyx of Held and its postsynaptic principal neuron in the medial nucleus of the trapezoid body. J. Neurosci. 22, 10567–10579 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Oertel, D. Encoding of timing in the brain stem auditory nuclei of vertebrates. Neuron 19, 959–962 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Trussell, L.O. Synaptic mechanisms for coding timing in auditory neurons. Annu. Rev. Physiol. 61, 477–496 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Kopp-Scheinpflug, C., Lippe, W.R., Dorrscheidt, G.J. & Rubsamen, R. The medial nucleus of the trapezoid body in the gerbil is more than a relay: comparison of pre- and postsynaptic activity. J. Assoc. Res. Otolaryngol. 4, 1–23 (2003).

    Article  PubMed  Google Scholar 

  14. Kanemasa, T., Perney, T.M., Gan, L., Wang, L.Y. & Kaczmarek, L.K. Electrophysiological and pharmacological characterization of a mammalian Shaw channel expressed in NIH 3T3 fibroblasts. J. Neurophysiol. 74, 207–217 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Wang, L.Y., Gan, L., Forsythe, I.D. & Kaczmarek, L.K. Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurons. J. Physiol. (Lond.) 509, 183–194 (1998).

    Article  CAS  Google Scholar 

  16. Rudy, B. et al. Contributions of the Kv3 channels to neuronal excitability. Ann. NY Acad. Sci. 868, 304–343 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Macica, C.M. et al. Modulation of the kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons. J. Neurosci. 23, 1133–1141 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parameshwaran-Iyer, S., Carr, C.E. & Perney, T.M. Localization of KCNC1 (Kv3.1) potassium channel subunits in the avian auditory nucleus magnocellularis and nucleus laminaris during development. J. Neurobiol. 55, 165–178 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. von Hehn, C.A., Bhattacharjee, A. & Kaczmarek, L.K. Loss of Kv3.1 tonotopicity and alterations in cAMP response element-binding protein signaling in central auditory neurons of hearing impaired mice. J. Neurosci. 24, 1936–1940 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Luneau, C.J. et al. Alternative splicing contributes to K+ channel diversity in the mammalian central nervous system. Proc. Natl. Acad. Sci. USA 88, 3932–3936 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ozaita, A., Martonem, M.E., Ellisman, M.H. & Rudy, B. Differential subcellular localization of the two alternatively spliced isoforms of the Kv3.1 potassium channel subunit in brain. J. Neurophysiol. 88, 394–408 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Critz, S.D., Wible, B.A., Lopez, H.S. & Brown, A.M. Stable expression and regulation of a rat brain K channel. J. Neurochem. 60, 1175–1178 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Paolini, A.G., FitzGerald, J.V., Burkitt, A.N. & Clark, G.M. Temporal processing from the auditory nerve to the medial nucleus of the trapezoid body in the rat. Hear. Res. 159, 101–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Parameshwaran, S., Carr, C.E. & Perney, T.M. Expression of the Kv3.1 potassium channel in the avian auditory brainstem. J. Neurosci. 21, 485–494 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, W., Kaczmarek, L.K. & Perney, T.M. Localization of two high-threshold potassium channel subunits in the rat central auditory system. J. Comp. Neurol. 437, 196–218 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Phillips, D.P. & Hall, S.E. Psychophysical evidence for adaptation of central auditory processors for interaural differences in time and level. Hear. Res. 202, 188–199 (2005).

    Article  PubMed  Google Scholar 

  27. Fujisaki, W., Shimojo, S., Kashino, M. & Nishida, S. Recalibration of audiovisual simultaneity. Nat. Neurosci. 7, 773–778 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Kopp-Scheinpflug, C., Dehmel, S., Dorrscheidt, G.J. & Rubsamen, R. Interaction of excitation and inhibition in anteroventral cochlear nucleus neurons that receive large endbulb synaptic endings. J. Neurosci. 22, 11004–11018 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sanes, D.H. An in vitro analysis of sound localization mechanisms in the gerbil lateral superior olive. J. Neurosci. 10, 3494–3506 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Grothe, B. & Park, T.J. Structure and function of the bat superior olivary complex. Microsc. Res. Tech. 51, 382–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Brand, A., Behrend, O., Marquardt, T., McAlpine, D. & Grothe, B. Precise inhibition is essential for microsecond interaural time difference coding. Nature 417, 543–547 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Augustine, C.K. & Bezanilla, F. Phosphorylation modulates potassium conductance and gating current of perfused giant axon of squid. J. Gen. Physiol. 95, 245–271 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Perozo, E. & Bezanilla, F. Phosphorylation affects voltage gating of the delayed rectifier K+ channel by electrostatic interactions. Neuron 5, 685–690 (1990).

    Article  CAS  PubMed  Google Scholar 

  34. Levitan, I.B. Modulation of ion channels by protein phosphorylation and dephosphorylation. Annu. Rev. Physiol. 56, 193–212 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Jonas, E.A. & Kaczmarek, L.K. Regulation of potassium channels by protein kinases. Curr. Opin. Neurobiol. 6, 318–323 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Misonou, H. et al. Regulation of ion channel localization and phosphorylation by neuronal activity. Nat. Neurosci. 7, 711–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, L.Y., Gan, L., Perney, T.M., Schwartz, I. & Kaczmarek, L.K. Activation of Kv3.1 channels in neuronal spine-like structures may induce local potassium ion depletion. Proc. Natl. Acad. Sci. USA 95, 1882–1887 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sommer, I., Lingenhohl, K. & Friauf, E. Principal cells of the rat medial nucleus of the trapezoid body: an intracellular in vivo study of their physiology and morphology. Exp. Brain Res. 95, 223–239 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Cohen, Y.E. & Saunders, J.C. The effect of acoustic overexposure on the tonotopic organization of the nucleus magnocellularis. Hear. Res. 81, 11–21 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Weiser, M. et al. Differential expression of Shaw-related K+ channels in the rat central nervous system. J. Neurosci. 14, 949–972 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Baranauskas, G., Tkatch, T., Nagata, K., Yeh, J.Z. & Surmeier, D.J. Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nat. Neurosci. 6, 258–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Moreno, H. et al. Thalamocortical projections have a K+ channel that is phosphorylated and modulated by cAMP-dependent protein kinase. J. Neurosci. 15, 5486–5501 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Atzori, M. et al. H2 histamine receptor-phosphorylation of Kv3.2 modulates interneuron fast spiking. Nat. Neurosci. 3, 791–798 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Covarrubias, M., Wei, A., Salkoff, L. & Vyas, T.B. Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate. Neuron 13, 1403–1412 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Antz, C. et al. Control of K+ channel gating by protein phosphorylation: structural switches of the inactivation gate. Nat. Struct. Biol. 6, 146–150 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Barnes-Davies, M., Barker, M.C., Osmani, F. & Forsythe, I.D. Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive. Eur. J. Neurosci. 19, 325–333 (2004).

    Article  PubMed  Google Scholar 

  47. Hamann, M., Billups, B. & Forsythe, I.D. Non-calyceal excitatory inputs mediate low fidelity synaptic transmission in rat auditory brainstem slices. Eur. J. Neurosci. 18, 2899–2902 (2003).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health grants DC01919 (L.K.K.) and DC00189 (D.L.O.) and the Wellcome Trust (I.D.F., M.H. & M.B.-D.). Part of this research was conducted in a facility constructed with support from Research Facilities Improvement grant C06 RR13551 from the National Center for Research Resources, US National Institutes of Health. We thank M. Browning of PhosphoSolutions for generation of the Kv3.1b phospho-specific antibody.

Author information

Author notes

  1. Margaret Barnes-Davies & Arin Bhattacharjee

    Present address: Department of Cell Physiology and Pharmacology and Medical and Social Care Education, University of Leicester, Leicester, LE1 9HN, UK

Authors and Affiliations

  1. Department of Pharmacology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Ping Song, Arin Bhattacharjee & Leonard K Kaczmarek

  2. Department of Neuroscience, University of Connecticut Health Center, Farmington, 06030, Connecticut, USA

    Yue Yang & Douglas L Oliver

  3. Department of Cell Physiology and Pharmacology, Medical Research Council Toxicology Unit, University of Leicester, Leicester, LE1 9HN, UK

    Margaret Barnes-Davies & Ian D Forsythe

  4. Cellular and Molecular Neuroscience Group, Medical Research Council Toxicology Unit, University of Leicester, Leicester, LE1 9HN, UK

    Martine Hamann

  5. Department of Pharmacology and Toxicology, The State University of New York at Buffalo, Buffalo, New York, 14214, USA

    Arin Bhattacharjee

Authors
  1. Ping Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margaret Barnes-Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arin Bhattacharjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martine Hamann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ian D Forsythe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Douglas L Oliver
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonard K Kaczmarek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonard K Kaczmarek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Phospho-Kv3.1b is present both pre- and post-synaptically in MNTB neurons. (PDF 174 kb)

Supplementary Fig. 2

Inhibition of AMPA and NMDA receptors attenuates stimulation-induced dephosphorylation of Kv3.1b channels. (PDF 250 kb)

Supplementary Fig. 3

Computer simulations of the effects of an increase in Kv3.1 conductance on the firing pattern of a representative model MNTB neuron. (PDF 35 kb)

Supplementary Fig. 4

Lack of significant change in the firing pattern of a real MNTB neuron that received no synaptic input. (PDF 40 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Song, P., Yang, Y., Barnes-Davies, M. et al. Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons. Nat Neurosci 8, 1335–1342 (2005). https://doi.org/10.1038/nn1533

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1533

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