Abstract
An increase in the concentration of protons in the synaptic cleft during neurotransmitters release is considered as one of the possible ways for postsynaptic membrane sensitization. The main sensors of acidification are acid-sensing ion channels (ASICs). The ASIC3 localized on the membrane of a sensing neuron contributes greatly to the perception of pain and is considered as one of the promising targets for the development of novel therapeutic agents. Despite a high degree of homology between mammalian ASIC3 channels, there is a number of differences among their orthologs. The major difference between human and rat ASIC3 is that, at physiological pH 7.4, the human ASIC3 responds to a fast acidic stimulus with practically a solitary sustained transmembrane current, while its rat ortholog generates a transient current with far higher amplitude, which precedes the sustained current. In this study, we demonstrate that the C-terminal intracellular domain (CTD) has a regulatory function, and its modification significantly affects transient current generation in human and rat ASIC3. A shortening of the CTD by 20 amino acid residues leads to a dramatic increase in the transient current and attenuation of the sustained current, while CTD modification in hASIC3 leads to the generation of a well-defined transient current like rASIC3, as demonstrated in whole-cell experiments on heterologically expressed channels. Furthermore, the deletion of 20 amino acid residues in the CTD increases the current amplitude by an order of magnitude both in rASIC3 and hASIC3. The obtained results demonstrate a prominent role of CTD in the intracellular regulation of ASIC3 channels.
Similar content being viewed by others
REFERENCES
Price, M.P., Gong, H., Parsons, M.G., Kundert, J.R., Reznikov, L.R., Bernardinelli, L., Chaloner, K., Buchanan, G.F., Wemmie, J.A., Richerson, G.B., Cassell, M.D., and Welsh, M.J., Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli, Genes Brain Behav., 2014, vol. 13, pp. 179–194. https://doi.org/10.1111/gbb.12108
Wemmie, J.A., Askwith, C.C., Lamani, E., Cassell, M.D., Freeman, J.H., and Welsh, M.J., Acid- sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning, J. Neurosci., 2003, vol. 23, pp. 5496–5502. https://doi.org/10.1523/JNEUROSCI.23-13-05496.2003
Alvarez de la Rosa, D., Zhang, P., Shao, D., White, F., and Canessa, C.M., Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system, Proc. Natl. Acad. Sci., 2002, vol. 99, pp. 2326–2331. https://doi.org/10.1073/pnas.042688199
Zha, X.-M., Wemmie, J.A., Green, S.H., and Welsh, M.J., Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines, Proc. Natl. Acad. Sci., 2006, vol. 103, pp. 16556–16561. https://doi.org/10.1073/pnas.0608018103
Liu, X., Liu, C., Ye, J., Zhang, S., Wang, K., and Su, R., Distribution of acid sensing ion channels in axonal growth cones and presynaptic membrane of cultured hippocampal neurons, Front. Cell Neurosci., 2020, vol. 14, pp. 205. https://doi.org/10.3389/fncel.2020.00205
Urbano, F.J., Lino, N.G., Gonzalez-Inchauspe, C.M.F., Gonzalez, L.E., Colettis, N., Vattino, L.G., Wunsch, A.M., Wemmie, J.A., and Uchitel, O.D., Acid-sensing ion channels 1a (ASIC1a) inhibit neuromuscular transmission in female mice, Am. J. Physiol. Physiol., 2014, vol. 306, pp. C396–C406. https://doi.org/10.1152/ajpcell.00301.2013
Cho, J.-H. and Askwith, C.C., Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice, J. Neurophysiol., 2008, vol. 99, pp. 426–441. https://doi.org/10.1152/jn.00940.2007
Du, J., Reznikov, L.R., Price, M.P., Zha, X.-m., Lu, Y., Moninger, T.O., Wemmie, J.A., and Welsh, M.J., Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala, Proc. Natl. Acad. Sci., 2014, vol. 111, pp. 8961–8966. https://doi.org/10.1073/pnas.1407018111
Kreple, C.J., Lu, Y., Taugher, R.J., Schwager-Gutman, A.L., Du, J., Stump, M., Wang, Y., Ghobbeh, A., Fan, R., Cosme, C.V., Sowers, L.P., Welsh, M.J., Radley, J.J., LaLumiere, R.T., and Wemmie, J.A., Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity, Nat. Neurosci., 2014, vol. 17, pp. 1083–1091. https://doi.org/10.1038/nn.3750
Giffard, R.G., Monyer, H., Christine, C.W., and Choi, D.W., Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures, Brain Res., 1990, vol. 506, pp. 339–342. https://doi.org/10.1016/0006-8993(90)91276-M
Traynelis, S.F. and Cull-Candy, S.G., Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons, Nature, 1990, vol. 345, pp. 347–350. https://doi.org/10.1038/345347a0
Tang, C.M., Dichter, M., and Morad, M., Modulation of the N-methyl-D-aspartate channel by extracellular H+, Proc. Natl. Acad. Sci., 1990, vol. 87, pp. 6445–6449. https://doi.org/10.1073/pnas.87.16.6445
Lei, S., Orser, B.A., Thatcher, G.R.L., Reynolds, J.N., and MacDonald, J.F., Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons, J. Neurophysiol., 2001, vol. 85, pp. 2030–2038. https://doi.org/10.1152/jn.2001.85.5.2030
Buta, A., Maximyuk, O., Kovalskyy, D., Sukach, V., Vovk, M., Ievglevskyi, O., Isaeva, E., Isaev, D., Savotchenko, A., and Krishtal, O., Novel potent orthosteric antagonist of ASIC1a prevents NMDAR-dependent LTP induction, J. Med. Chem., 2015, vol. 58, pp. 4449–4461. https://doi.org/10.1021/jm5017329
Liu, M.-G., Li, H.-S., Li, W.-G., Wu, Y.-J., Deng, S.-N., Huang, C., Maximyuk, O., Sukach, V., Krishtal, O., Zhu, M.X., and Xu, T.-L., Acid-sensing ion channel 1a contributes to hippocampal LTP inducibility through multiple mechanisms, Sci. Rep., 2016, vol. 6, p. 23350. https://doi.org/10.1038/srep23350
Ma, C.-L., Sun, H., Yang, L., Wang, X.-T., Gao, S., Chen, X.-W., Ma, Z.-Y., Wang, G., Shi, Z., and Zheng, Q.-Y., Acid-sensing ion channel 1a modulates NMDA receptor function through targeting NR1/NR2A/NR2B triheteromeric receptors, Neuroscience, 2019, vol. 406, pp. 389–404. https://doi.org/10.1016/j.neuroscience.2019.03.044
Mango, D., Braksator, E., Battaglia, G., Marcelli, S., Mercuri, N.B., Feligioni, M., Nicoletti, F., Bashir, Z.I., and Nistico, R., Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus, Pharmacol. Res., 2017, vol. 119, pp. 12–19. https://doi.org/10.1016/j.phrs.2017.01.028
Gonzalez-Inchauspe, C., Urbano, F.J., Di Guilmi, M.N., and Uchitel, O.D., Acid-sensing ion channels activated by evoked released protons modulate synaptic transmission at the mouse calyx of held synapse, J. Neurosci., 2017, vol. 37, pp. 2589–2599. https://doi.org/10.1523/JNEUROSCI.2566-16.2017
Blaustein, M., Wirth, S., Saldana, G., Piantanida, A.P., Bogetti, M.E., Martin, M.E., Colman-Lerner, A., and Uchitel, O.D., A new tool to sense pH changes at the neuromuscular junction synaptic cleft, Sci. Rep., 2020, vol. 10, p. 20480. https://doi.org/10.1038/s41598-020-77154-3
Osmakov, D.I., Koshelev, S.G., Andreev, Y.A., and Kozlov, S.A., Endogenous isoquinoline alkaloids agonists of acid-sensing ion channel type 3, Front Mol. Neurosci., 2017, vol. 10, p. 282. https://doi.org/10.3389/FNMOL.2017.00282
Osmakov, D.I., Koshelev, S.G., Andreev, Y.A., Dubinnyi, M.A., Kublitski, V.S., Efremov, R.G., Sobolevsky, A.I., and Kozlov, S.A., Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis, Br. J. Pharmacol., 2018, vol. 175, pp. 924–937. https://doi.org/10.1111/bph.14134
Osmakov, D.I., Khasanov, T.A., Andreev, Y.A., Lyukmanova, E.N., and Kozlov, S.A., Animal, herb, and microbial toxins for structural and pharmacological study of acid-sensing ion channels, Front Pharmacol., 2020, vol. 11, p. 991. https://doi.org/10.3389/fphar.2020.00991
Shteinikov, V., Potapieva, N., Gmiro, V., and Tikhonov, D., Hydrophobic amines and their guanidine analogues modulate activation and desensitization of ASIC3, Int. J. Mol. Sci., 2019, vol. 20, p. 1713. https://doi.org/10.3390/ijms20071713
Highstein, S.M., Holstein, G.R, Mann, M.A., and Rabbitt, R.D., Evidence that protons act as neurotransmitters at vestibular hair cell-calyx afferent synapses, Proc. Natl. Acad. Sci., 2014, vol. 111, pp. 5421–5426. https://doi.org/10.1073/pnas.1319561111
Yoder, N., Yoshioka, C., and Gouaux, E., Gating mechanisms of acid-sensing ion channels, Nature, 2018, vol. 555, pp. 397–401. https://doi.org/10.1038/nature25782
Wang, S., Peng, J., Ma, J., and Xu, J., Protein secondary structure prediction using deep convolutional neural fields, Sci. Rep., 2016, vol. 6, p. 18962. https://doi.org/10.1038/srep18962
Klipp, R.C., Cullinan, M.M., and Bankston, J.R., Insights into the molecular mechanisms underlying the inhibition of acid-sensing ion channel 3 gating by stomatin, J. Gen. Physiol., 2020, vol. 152(3), p. e201912471. https://doi.org/10.1085/jgp.201912471
Osmakov, D.I., Koshelev, S.G., Ivanov, I.A., Andreev, Y.A., and Kozlov, S.A., Endogenous neuropeptide nocistatin is a direct agonist of acid-sensing ion channels (ASIC1, ASIC2 and ASIC3), Biomolecules, 2019, vol. 9 (9), p. 401. https://doi.org/10.3390/biom9090401
Waldmann, R., Bassilana, F., de Weille, J., Champigny, G., Heurteaux, C., and Lazdunski, M., Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons, J. Biol. Chem., 1997, vol. 272, pp. 20975–20978. https://doi.org/10.1074/jbc.272.34.20975
Grunder, S. and Pusch, M., Biophysical properties of acid-sensing ion channels (ASICs), Neuropharmacology, 2015, vol. 94, pp. 9–18. https://doi.org/10.1016/j.neuropharm.2014.12.016
Price, M.P., Thompson, R.J., Eshcol, J.O., Wemmie, J.A., and Benson, C.J., Stomatin modulates gating of acid-sensing ion channels, J. Biol. Chem., 2004, vol. 279, pp. 53886–53891. https://doi.org/10.1074/jbc.M407708200
Goodman, M.B., Ernstrom, G.G., Chelur, D.S., O’Hagan, R., Yao, C.A., and Chalfie, M., MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation, Nature, 2002, vol. 415, pp. 1039–1042. https://doi.org/10.1038/4151039a
ACKNOWLEDGMENTS
The authors are grateful to Sylvie Diochot (Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France) for providing the PCi plasmid containing the rat ASIC3 cDNA.
Author information
Authors and Affiliations
Contributions
Experiment design (D.I.O., Yu.V.K., S.A.K.); biochemical experiments and obtaining a recombinant peptide (E.E.M.); molecular cloning and creating mutant constructs (Yu.V.K., Ya.A.A., K.I.L.); electrophysiological studies on oocytes (D.I.O., K.I.L.); project supervision (S.A.K.); data analysis and manuscript writing (D.I.O., Yu.V.K., Ya.A.A., S.A.K.). All the authors have read and agreed with the published version of the manuscript.
Corresponding author
Ethics declarations
CONFLICT OF INTEREST
The authors declare that they have no evident or potential conflict of interest related with the publication of this work.
Additional information
Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, Nos. 4–5, pp. 616–628https://doi.org/10.31857/S0869813921040129.
Translated by A. Polyanovsky
Rights and permissions
About this article
Cite this article
Osmakov, D.I., Korolkova, Y.V., Lubova, K.I. et al. The Role of the C-terminal Intracellular Domain in Acid-Sensing Ion Channel 3 Functioning. J Evol Biochem Phys 57, 413–423 (2021). https://doi.org/10.1134/S0022093021020204
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0022093021020204