Physiological and Pharmacological Characteristics of Native Proton-Activated Ion Channels

  • T. B. TikhonovaEmail author
  • O. I. Barygin

Proton-activated ion channels (ASICs) are widely distributed in the CNS and take part in many physiological processes. We report here studies characterizing pH-induced currents in various neuron types. Overall, the data provide evidence that currents in all these neurons are mediated mainly by heterodimeric ASICs; interneurons in the striatum radiatum of the hippocampus, pyramidal neurons in layer 2 of the medial prefrontal cortex, and interneurons in the striatum have receptors with weak pH sensitivity and pharmacological profiles combining the features of both ASIC1a and ASIC2a subunits. Pyramidal cells in layer 3 of the medial prefrontal cortex also have the same pharmacological profile but greater sensitivity to protons. In cerebellar Purkinje cells, heteromeric receptors are formed mainly from ASIC1a and ASIC2b subunits, as there is no sensitivity to ASIC2a-specific ligands though currents are induced by weak acidification.


proton-activated channels monoamines interneuron interactions subunit composition 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D. Alvarez de la Rosa, S. R. Krueger, A. Kolar, et al., “Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system,” J. Physiol., 546, No. 1, 77–87 (2003).CrossRefGoogle Scholar
  2. 2.
    K. Babinski, S. Catarsi, G. Biagini, and P. Seguela, “Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-gated channels sensitive to Gd3+,” J. Biol. Chem., 275, 28519–28525 (2000).CrossRefGoogle Scholar
  3. 3.
    A. Baron, L. Schaefer, E. Lingueglia, et al., “Zn2+ and H+ are coactivators of acid-sensing ion channels,” J. Biol. Chem., 276, 35361–35367 (2001).CrossRefGoogle Scholar
  4. 4.
    F. Bassilana, G. Champigny, R. Waldmann, et al., “Acid-sensitive ionic channel subunit ASIC and the mammalian degenerin MDEG form a heteromultimeric H+-gated Na+ channel with novel properties,” J. Biol. Chem., 272, No. 46, 28819–28822 (1997).CrossRefGoogle Scholar
  5. 5.
    C. J. Benson, J. Xie, J. A. Wemmie, et al., “Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons,” Proc. Natl. Acad. Sci. USA, 99, No. 4, 2338–2343 (2002).CrossRefGoogle Scholar
  6. 6.
    N. Boiko, V. Kucher, B. Wang, and J. D. Stockand, “Restrictive expression of acid-sensing ion channel 5 (Asic5) in unipolar brush cells of the vestibulocerebellum,” PLoS One, 9, No. 3, e91326 (2014).CrossRefGoogle Scholar
  7. 7.
    K. V. Bolshakov, K. V. Essin, S. L. Buldakova, et al., “Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons,” Neuroscience, 110, No. 4, 723–730 (2002).CrossRefGoogle Scholar
  8. 8.
    G. Champigny, N. Voilley, R. Waldmann, and M. Lazdunski, “Mutations causing neurodegeneration in Caenorhabditis elegans drastically alter the pH sensitivity and inactivation of the mammalian H+-gated Na+ channel MDEG1,” J. Biol. Chem., 273, No. 25, 15418–15422 (1998).CrossRefGoogle Scholar
  9. 9.
    P. H. Chiang, T. C. Chien, C. C. Chen, et al., “ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory,” Sci. Rep., 5, 10143 (2014), doi: Scholar
  10. 10.
    X. P. Chu, J. A. Wemmie, W. Z. Wang, et al., “Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels,” J. Neurosci., 24, 8678–8689 (2004).CrossRefGoogle Scholar
  11. 11.
    P. Escoubas, J. R. DeWeille, A. Lecoq, et al., “Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels,” J. Biol. Chem., 275, 25116–25121 (2000).CrossRefGoogle Scholar
  12. 12.
    M. Farrant and S. G. Cull-Candy, “Excitatory amino acid receptor-channels in Purkinje cells in thin cerebellar slices,” Proc. Biol. Sci., 244, 179–184 (1991).CrossRefGoogle Scholar
  13. 13.
    J. Gao, B. Duan, D. G. Wang, et al., “Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic Neuronal death,” Neuron, 48, No. 4, 635–646 (2005).CrossRefGoogle Scholar
  14. 14.
    J. Garcia-Anoveros, B. Derfler, J. Neville-Golden, et al., “BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels,” Proc. Natl. Acad. Sci. USA, 94, No. 4, 1459–1464 (1997).CrossRefGoogle Scholar
  15. 15.
    M. Gautam and C. Benson, “Acid-sensing ion channels (ASICs) in mouse skeletal muscle afferents are heteromers composed of ASICla, ASIC2, and ASIC3 subunits,” FASEB J., 27, No. 2, 793–802 (2013).CrossRefGoogle Scholar
  16. 16.
    J. Hartmann and A. Konnerth, “Determinants of postsynaptic Ca2+ signaling in Purkinje neurons,” Cell Calcium, 37, 459–466 (2005).CrossRefGoogle Scholar
  17. 17.
    M. Hesselager, D. B. Timmermann, and P. K. Ahring, “pH Dependency and desensitization kinetics of heterologously expressed combinations of acid-sensing ion channel subunits,” J. Biol. Chem., 279, No. 12, 11006–11015 (2004).CrossRefGoogle Scholar
  18. 18.
    N. Joeres, K. Augustinowski, A. Neuhof, et al., “Functional and pharmacological characterization of two different ASIC1a/2a heteromers reveals their sensitivity to the spider toxin PcTx1,” Sci. Rep., 6, 27647 (2016), doi: Scholar
  19. 19.
    C. J. Kreple, Y. Lu, R. J. Taugher, et al., “Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity,” Nat. Neurosci., 17, No. 8, 1083–1091 (2014).CrossRefGoogle Scholar
  20. 20.
    B. Lambolez, E. Audinat, P. Bochet, et al., “AMPA receptor subunits expressed by single Purkinje cells,” Neuron, 9, 247–258 (1992).CrossRefGoogle Scholar
  21. 21.
    E. Lingueglia, J. R. de Weille, F. Bassilana, et al., “A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells,” J. Biol. Chem., 272, No. 47, 29778–29783 (1997).CrossRefGoogle Scholar
  22. 22.
    E. Lingueglia, “Acid-sensing ion channels in sensory perception,” J. Biol. Chem., 282, 17,325–17,329 (2007).CrossRefGoogle Scholar
  23. 23.
    L. G. Magazanik, S. L. Buldakova, M. V. Samoilova, et al., “Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives,” J. Physiol., 505, No. 3, 655–663 (1997).CrossRefGoogle Scholar
  24. 24.
    E. I. Nagaeva, T. B. Tikhonova, L. G. Magazanik, and D. B. Tikhonov, “Histamine selectively potentiates acid sensing ion channels,” Neurosci. Lett., 632, 136–140 (2016).CrossRefGoogle Scholar
  25. 25.
    M. P. Price, P. M. Snyder, and M. J. Welsh, “Cloning and expression of a novel human brain Na1 channel,” J. Biol. Chem., 271, No. 14, 7879–7882 (1996).CrossRefGoogle Scholar
  26. 26.
    T. B. Tikhonova, E. I. Nagaeva, O. I. Barygin, et al., “Monoamine NMDA receptor channel blockers inhibit and potentiate native and recombinant proton-gated ion channels,” Neuropharmacology, 89, 1–10 (2015).CrossRefGoogle Scholar
  27. 27.
    V. S. Vorobjev, “Vibrodissociation of sliced mammalian nervous tissue,” J. Neurosci. Meth., 68, 303–307 (1991).CrossRefGoogle Scholar
  28. 28.
    R. Waldmann, G. Champigny, F. Bassilana, et al., “A proton-gated cation channel involved in acid-sensing,” Nature, 386, No. 6621, 173–177 (1997).CrossRefGoogle Scholar
  29. 29.
    J. A. Wemmie, C. C. Askwith, E. Lamani, et al., “Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning,” J. Neurosci., 23, No. 13, 5496–5502 (2003).CrossRefGoogle Scholar
  30. 30.
    J. A. Wemmie, J. Chen, C. C. Askwith, et al., “The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory,” Neuron, 34, No. 3, 463–477 (2002).CrossRefGoogle Scholar
  31. 31.
    J. A. Wemmie, M. W. Coryell, C. C. Askwith, et al., “Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior,” Proc. Natl. Acad. Sci. USA, 101, No. 10, 3621–3626 (2004).CrossRefGoogle Scholar
  32. 32.
    J. Y. Weng, Y. C. Lin, and C. C. Lien, “Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons,” J. Neurosci., 30, No. 19, 6548–6558 (2010).CrossRefGoogle Scholar
  33. 33.
    J. Wu, Y. Xu, Y. Q. Jiang, et al., “ASIC subunit ratio and differential surface trafficking in the brain,” Mol. Brain, 9, 4 (2016), Scholar
  34. 34.
    A. E. Ziemann, J. E. Allen, N. S. Dahdaleh, et al., “The amygdala is a chemo-sensor that detects carbon dioxide and acidosis to elicit fear behavior,” Cell, 139, No. 5, 1012–1021 (2009).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sechenov institute of Evolutionary Physiology and BiochemistryRussian Academy of Sciences (IEPhB RAS)St. PetersburgRussia

Personalised recommendations