González-Inchauspe, C.; Urbano, F.J.; Di Guilmi, M.N.; Uchitel, O.D."Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse" (2017) Journal of Neuroscience. 37(10):2589-2599
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. We found that these channels can be activated in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. A drop in extracellular pH induces transient inward ASIC currents (IASICs) in postsynaptic MNTB neurons from wild-type mice. The inhibition of IASICs by psalmotoxin-1 (PcTx1) and the absence of these currents in knock-out mice for ASIC-1a subunit (ASIC1a-/-) suggest that homomeric ASIC-1as are mediating these currents in MNTB neurons. Furthermore, we detect ASIC1a-dependent currents during synaptic transmission, suggesting an acidification of the synaptic cleft due to the corelease of neurotransmitter and H+ from synaptic vesicles. These currents are capable of eliciting action potentials in the absence of glutamatergic currents. A significant characteristic of these homomeric ASIC-1as is their permeability to Ca2+. Activation of ASIC-1a in MNTB neurons by exogenous H+ induces an increase in intracellular Ca2+. Furthermore, the activation of postsynaptic ASIC-1as during high-frequency stimulation (HFS) of the presynaptic nerve terminal leads to a PcTx1-sensitive increase in intracellular Ca2+ in MNTB neurons, which is independent of glutamate receptors and is absent in neurons from ASIC1a-/-mice. During HFS, the lack of functional ASICs in synaptic transmission results in an enhanced short-term depression of glutamatergic EPSCs. These results strongly support the hypothesis of protons as neurotransmitters and demonstrate that presynaptic released protons modulate synaptic transmission by activating ASIC-1as at the calyx of Held-MNTB synapse. © 2017 the authors.


Documento: Artículo
Título:Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse
Autor:González-Inchauspe, C.; Urbano, F.J.; Di Guilmi, M.N.; Uchitel, O.D.
Filiación:Instituto de Fisiología Biología molecular y Neurociencias, Departamento de Fisiología Biología Molecular y Celular “Dr Héctor Maldonado”, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, EGA, Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, Beunos Aires, CP 1428, Argentina
Palabras clave:ASIC-1a; Calyx of held; Glutamatergic EPSCs; Protons; Short-term depression; Synaptic plasticity; acid sensing ion channel; amiloride; AMPA receptor; antiporter; creatine phosphate; glutamate receptor; glutamic acid; postsynaptic receptor; Accn2 protein, mouse; acid sensing ion channel; proton; acidification; action potential; animal experiment; Article; cell membrane permeability; depolarization; depression; desensitization; drug mechanism; electrophysiology; evoked response; female; fluorescence; glutamatergic synapse; male; mouse; nerve cell plasticity; nerve ending; neurotransmitter release; nonhuman; patch clamp technique; priority journal; synapse; synaptic transmission; animal; auditory evoked potential; C57BL mouse; channel gating; chemistry; cochlear nucleus; metabolism; pH; physiology; synapse; synaptic transmission; Acid Sensing Ion Channels; Animals; Cochlear Nucleus; Evoked Potentials, Auditory; Female; Hydrogen-Ion Concentration; Ion Channel Gating; Male; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Protons; Synapses; Synaptic Transmission
Página de inicio:2589
Página de fin:2599
Título revista:Journal of Neuroscience
Título revista abreviado:J. Neurosci.
CAS:amiloride, 2016-88-8, 2609-46-3; creatine phosphate, 67-07-2; glutamic acid, 11070-68-1, 138-15-8, 56-86-0, 6899-05-4; proton, 12408-02-5, 12586-59-3; Accn2 protein, mouse; Acid Sensing Ion Channels; Protons


  • Baron, A., Deval, E., Salinas, M., Lingueglia, E., Voilley, N., Lazdunski, M., Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1 (2002) J Biol Chem, 277, pp. 50463-50468
  • Baron, A., Voilley, N., Lazdunski, M., Lingueglia, E., Acid sensing ion channels in dorsal spinal cord neurons (2008) J Neurosci, 28, pp. 1498-1508
  • Cens, T., Rousset, M., Charnet, P., Two sets of amino acids of the domain I of Cav2.3 Ca channels contribute to their high sensitivity to extracellular protons (2011) Pflugers Arch, 462, pp. 303-314
  • Chen, C.C., England, S., Akopian, A.N., Wood, J.N., A sensory neuron-specific, proton-gated ion channel (1998) Proc Natl Acad Sci U S A, 95, pp. 10240-10245
  • Chen, X., Kalbacher, H., Grunder, S., Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent (2006) J Gen Physiol, 127, pp. 267-276
  • Chesler, M., Regulation and modulation of pH in the brain (2003) Physiol Rev, 83, pp. 1183-1221
  • Cho, J.H., Askwith, C.C., Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice (2008) J Neurophysiol, 99, pp. 426-441
  • Cho, S., Von Gersdorff, H., Proton-mediated block of Ca channels during multivesicular release regulates short-term plasticity at an auditory hair cell synapse (2014) J Neurosci, 34, pp. 15877-15887
  • Chu, X.P., Xiong, Z.G., Physiological and pathological functions of acid-sensing ion channels in the central nervous system (2012) Curr Drug Targets, 13, pp. 263-271
  • Chu, X.P., Wemmie, J.A., Wang, W.Z., Zhu, X.M., Saugstad, J.A., Price, M.P., Simon, R.P., Xiong, Z.G., Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels (2004) J Neurosci, 24, pp. 8678-8689
  • Devries, S.H., Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors (2001) Neuron, 32, pp. 1107-1117
  • Du, J., Reznikov, L.R., Price, M.P., Zha, X.M., Lu, Y., Moninger, T.O., Wemmie, J.A., Welsh, M.J., Protons and ASICs are a neurotransmitter/receptor pair that regulates synaptic plasticity in the lateral amygdala (2014) Proc Natl Acad Sci U S A, 111, pp. 8961-8966
  • Escoubas, P., De Weille, J.R., Lecoq, A., Diochot, S., Waldmann, R., Champigny, G., Moinier, D., Lazdunski, M., Isolation of a tarantula toxin specific for a class of proton-gated Na channels (2000) J Biol Chem, 275, pp. 25116-25121
  • Friese, M.A., Craner, M.J., Etzensperger, R., Vergo, S., Wemmie, J.A., Welsh, M.J., Vincent, A., Fugger, L., Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system (2007) Nat Med, 13, pp. 1483-1489
  • Grunder, S., Pusch, M., Biophysical properties of acid-sensing ion channels (ASICs) (2015) Neuropharmacology, 94, pp. 9-18
  • Hnasko, T.S., Edwards, R.H., Neurotransmitter corelease: Mechanism and physiological role (2012) Annu Rev Physiol, 74, pp. 225-243
  • Hruska-Hageman, A.M., Wemmie, J.A., Price, M.P., Welsh, M.J., Interaction of the synaptic protein PICK1 (Protein interacting with C kinase 1) with the non-voltage gated sodium channels BNC1 (brain Na channel 1) and ASIC (acid-sensing ion channel) (2002) Biochem J, 361, pp. 443-450
  • Huang, C., Hu, Z.L., Wu, W.N., Yu, D.F., Xiong, Q.J., Song, J.R., Shu, Q., Chen, J.G., Existence and distinction of acid-evoked currents in rat astrocytes (2010) Glia, 58, pp. 1415-1424
  • Huang, Y., Jiang, N., Li, J., Ji, Y.H., Xiong, Z.G., Zha, X.M., Two aspects of ASIC function: Synaptic plasticity and neuronal injury (2015) Neuropharmacology, 94, pp. 42-48
  • Ihle, E.C., Patneau, D.K., Modulation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization by extracellular protons (2000) Mol Pharmacol, 58, pp. 1204-1212
  • Jin, W., Shen, C., Jing, L., Zha, X.M., Xia, J., PICK1 regulates the trafficking of ASIC1a and acidotoxicity in a BAR domain lipid binding-dependent manner (2010) Mol Brain, 3, p. 39
  • Kellenberger, S., Schild, L., International Union of Basic and Clinical Pharmacology. XCI. Structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na channel (2015) Pharmacol Rev, 67, pp. 1-35
  • Kreple, C.J., Lu, Y., Taugher, R.J., Schwager-Gutman, A.L., Du, J., Stump, M., Wang, Y., Wemmie, J.A., Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity (2014) Nat Neurosci, 17, pp. 1083-1091
  • Krishtal, O., The ASICs: Signaling molecules? Modulators? (2003) Trends Neurosci, 26, pp. 477-483
  • Krishtal, O.A., Osipchuk, Y.V., Shelest, T.N., Smirnoff, S.V., Rapid extracel-lular pH transients related to synaptic transmission in rat hippocampal slices (1987) Brain Res, 436, pp. 352-356
  • Lei, S., Orser, B.A., Thatcher, G.R., Reynolds, J.N., Macdonald, J.F., Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons (2001) J Neurophysiol, 85, pp. 2030-2038
  • Li, T., Yang, Y., Canessa, C.M., Impact of recovery from desensitization on acid-sensing ion channel-1a (ASIC1a) current and response to high frequency stimulation (2012) J Biol Chem, 287, pp. 40680-40689
  • Lilley, S., Letissier, P., Robbins, J., The discovery and characterization of a proton-gated sodium current in rat retinal ganglion cells (2004) J Neurosci, 24, pp. 1013-1022
  • Lingueglia, E., De Weille, J.R., Bassilana, F., Heurteaux, C., Sakai, H., Waldmann, R., Lazdunski, M., A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells (1997) J Biol Chem, 272, pp. 29778-29783
  • Maclean, D.M., Jayaraman, V., Acid-sensing ion channels are tuned to follow high-frequency stimuli (2016) J Physiol, 594, pp. 2629-2645
  • Miesenböck, G., De Angelis, D.A., Rothman, J.E., Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins (1998) Nature, 394, pp. 192-195
  • Palmer, M.J., Hull, C., Vigh, J., Von Gersdorff, H., Synaptic cleft acidifica-tion and modulation of short-term depression by exocytosed protons in retinal bipolar cells (2003) J Neurosci, 23, pp. 11332-11341
  • Medline Price, M.P., Gong, H., Parsons, M.G., Kundert, J.R., Reznikov, L.R., Bernardinelli, L., Chaloner, K., Welsh, M.J., Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli (2014) Genes Brain Behav, 13, pp. 179-194
  • Renden, R., Taschenberger, H., Puente, N., Rusakov, D.A., Duvoisin, R., Wang, L.Y., Lehre, K.P., Von Gersdorff, H., Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of Held synapses (2005) J Neurosci, 25, pp. 8482-8497
  • Reyes-Haro, D., Muller, J., Boresch, M., Pivneva, T., Benedetti, B., Scheller, A., Nolte, C., Kettenmann, H., Neuron-astrocyte interactions in the medial nucleus of the trapezoid body (2010) J Gen Physiol, 135, pp. 583-594
  • Shah, M.J., Meis, S., Munsch, T., Pape, H.C., Modulation by extracellular pH of low-and high-voltage-activated calcium currents of rat thalamic relay neurons (2001) J Neurophysiol, 85, pp. 1051-1058
  • Trapp, S., Luckermann, M., Kaila, K., Ballanyi, K., Acidosis of hippocam-pal neurons mediated by a plasmalemmal Ca2/H pump (1996) Neuroreport, 7, pp. 2000-2004
  • Trapp, S., Luckermann, M., Brooks, P.A., Ballanyi, K., Acidosis of rat dorsal vagal neurons in situ during spontaneous and evoked activity (1996) J Physiol, 496, pp. 695-710
  • Traynelis, S.F., Cull-Candy, S.G., Pharmacological properties and H sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones (1991) J Physiol, 433, pp. 727-763
  • Urbano, F.J., Lino, N.G., González-Inchauspe, C., González, L.E., Colettis, N., Vattino, L.G., Wunsch, A.M., Uchitel, O.D., Acid-sensing ion channels 1a (ASIC1a) inhibit neuromuscular transmission in female mice (2014) Am J Physiol Cell Physiol, 306, pp. 396-406
  • Vessey, J.P., Stratis, A.K., Daniels, B.A., Da Silva, N., Jonz, M.G., Lalonde, M.R., Baldridge, W.H., Barnes, S., Proton-mediated feedback inhibition of presynaptic calcium channels at the cone photoreceptor synapse (2005) J Neu-Rosci, 25, pp. 4108-4117
  • Waldmann, R., Lazdunski, M., H(+)-gated cation channels: Neuronal acid sensors in the NaC/DEG family of ion channels (1998) Curr Opin Neurobiol, 8, pp. 418-424
  • Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C., Lazdunski, M., A proton-gated cation channel involved in acid-sensing (1997) Nature, 386, pp. 173-177
  • Waldmann, R., Bassilana, F., De Weille, J., Champigny, G., Heurteaux, C., Lazdun-Ski, M., Molecular cloning of a non-inactivating proton-gated Na channel specific for sensory neurons (1997) J Biol Chem, 272, pp. 20975-20978
  • Wemmie, J.A., Chen, J., Askwith, C.C., Hruska-Hageman, A.M., Price, M.P., Nolan, B.C., Yoder, P.G., Welsh, M.J., The acid activated ion channel ASIC contributes to synaptic plasticity, learn-ing, and memory (2002) Neuron, 34, pp. 463-477
  • Wemmie, J.A., Askwith, C.C., Lamani, E., Cassell, M.D., Freeman, J.H., Jr., Welsh, M.J., Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning (2003) J Neurosci, 23, pp. 5496-5502
  • Wemmie, J.A., Price, M.P., Welsh, M.J., Acid-sensing ion channels: Ad-vances, questions and therapeutic opportunities (2006) Trends Neurosci, 29, pp. 578-586
  • Wu, L.J., Duan, B., Mei, Y.D., Gao, J., Chen, J.G., Zhuo, M., Xu, L., Xu, T.L., Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord (2004) J Biol Chem, 279, pp. 43716-43724
  • Xiong, Z.G., Zhu, X.M., Chu, X.P., Minami, M., Hey, J., Wei, W.L., Macdonald, J.F., Simon, R.P., Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels (2004) Cell, 118, pp. 687-698
  • Xiong, Z.G., Chu, X.P., Simon, R.P., Ca 2-permeable acid-sensing ion channels and ischemic brain injury (2006) J Membr Biol, 209, pp. 59-68
  • Yermolaieva, O., Leonard, A.S., Schnizler, M.K., Abboud, F.M., Welsh, M.J., Extracellular acidosis increases neuronal cell calcium by activating acid sensing ion channel 1a (2004) Proc Natl Acad Sci U S A, 101, pp. 6752-6757
  • Zha, X.M., Acid-sensing ion channels: Trafficking and synaptic function (2013) Mol Brain, 6, p. 1
  • Ziemann, A.E., Schnizler, M.K., Albert, G.W., Severson, M.A., Howard, M.A., Welsh, M.J., Wemmie, J.A., Seizure termination by acidosis depends on ASIC1a (2008) Nat Neurosci, 11, pp. 816-822


---------- APA ----------
González-Inchauspe, C., Urbano, F.J., Di Guilmi, M.N. & Uchitel, O.D. (2017) . Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse. Journal of Neuroscience, 37(10), 2589-2599.
---------- CHICAGO ----------
González-Inchauspe, C., Urbano, F.J., Di Guilmi, M.N., Uchitel, O.D. "Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse" . Journal of Neuroscience 37, no. 10 (2017) : 2589-2599.
---------- MLA ----------
González-Inchauspe, C., Urbano, F.J., Di Guilmi, M.N., Uchitel, O.D. "Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse" . Journal of Neuroscience, vol. 37, no. 10, 2017, pp. 2589-2599.
---------- VANCOUVER ----------
González-Inchauspe, C., Urbano, F.J., Di Guilmi, M.N., Uchitel, O.D. Activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse. J. Neurosci. 2017;37(10):2589-2599.