Endosomal pH in neuronal signaling and synaptic transmission: Role of Na+/H+ exchanger NHE5

Frontiers in Physiology

Volumn 4 JAN, Issue , 2014, Pages

  Diering, Graham H ^a   Numata, Masayuki ^b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Dendritic spines; Endocytic recycling; Neurites; Neurotrophins; NMDA receptor; Protons; Signaling endosomes; Trk receptors

Indexed keywords

EID: 84893479572     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2013.00412     Document Type: Review

References (105)

1. 2+ current and low threshold K+ current in hair cells. Neurochem. Res. 33, 1435-1441. doi: 10.1007/s11064-007-9565-9.
2. Arimura, N., Kimura, T., Nakamuta, S., Taya, S., Funahashi, Y., Hattori, A., et al. (2009). Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev. Cell 16, 675-686. doi: 10.1016/j.devcel.2009.03.005.
3. +-Hl. exchanger. Annu. Rev. Physiol. 47, 545-560. doi: 10.1146/annurev.ph.47.030185.002553.
4. Ascano, M., Richmond, A., Borden, P., and Kuruvilla, R. (2009). Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses. J. Neurosci. 29, 11674-11685. doi: 10.1523/JNEUROSCI.1542-09.2009.
5. + exchanger (NHE5) highly expressed in brain. J. Biol. Chem. 274, 4383-4388. doi: 10.1074/jbc.274.7.4383.
6. Baird, N. R., Orlowski, J., Szabo, E. Z., Zaun, H. C., Schultheis, P. J., Menon, A. G., et al. (1999). Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brain. J. Biol. Chem. 274, 4377-4382. doi: 10.1074/jbc.274.7.4377.
7. Banke, T. G., Dravid, S. M., and Traynelis, S. F. (2005). Protons trap NR1/NR2B NMDA receptors in a nonconducting state. J. Neurosci. 25, 42-51. doi: 10.1523/JNEUROSCI.3154-04.2005.
8. Baxter, K. A., and Church, J. (1996). Characterization of acid extrusion mechanisms in cultured fetal rat hippocampal neurones. J. Physiol. 493 (pt 2), 457-470.
9. Brett, C. L., Donowitz, M., and Rao, R. (2005). Evolutionary origins of eukaryotic sodium/proton exchangers. Am. J. Physiol. Cell Physiol. 288, C223-C239. doi: 10.1152/ajpcell.00360.2004.
10. Casey, J. R., Grinstein, S., and Orlowski, J. (2010). Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 11, 50-61. doi: 10.1038/nrm2820.
11. Chao, M. V. (2003). Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4, 299-309. doi: 10.1038/nrn1078.
12. Chesler, M. (2003). Regulation and modulation of pH in the brain. Physiol. Rev. 83, 1183-1221. doi: 10.1152/physrev.00010.2003.
13. Chesler, M., and Kaila, K. (1992). Modulation of pH by neuronal activity. Trends Neurosci. 15, 396-402. doi: 10.1016/0166-2236(92)90191-A.
14. Cox, G. A., Lutz, C. M., Yang, C. L., Biemesderfer, D., Bronson, R. T., Fu, A., et al. (1997). Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91, 139-148. doi: 10.1016/S0092-8674(01)80016-7.
15. Deane, E. C., Ilie, A. E., Sizdahkhani, S., Das Gupta, M., Orlowski, J., and Mckinney, R. A. (2013). Enhanced recruitment of endosomal Na+/H+ Exchanger NHE6 into dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. J. Neurosci. 33, 595-610. doi: 10.1523/JNEUROSCI.2583-12.2013.
16. Diering, G. H., Mills, F., Bamji, S. X., and Numata, M. (2011). Regulation of dendritic spine growth through activity-dependent recruitment of the brain-enriched Na+/H+ exchanger NHE5. Mol. Biol. Cell 22, 2246-2257. doi: 10.1091/mbc.E11-01-0066.
17. Diering, G. H., Numata, Y., Fan, S., Church, J., and Numata, M. (2013). Endosomal acidification by Na+/H+ exchanger NHE5 regulates TrkA cell-surface targeting and NGF-induced PI3K signaling. Mol. Biol. Cell 24, 3435-3448. doi: 10.1091/mbc.E12-06-0445.
18. Dietrich, C. J., and Morad, M. (2010). Synaptic acidification enhances GABAA signaling. J. Neurosci. 30, 16044-16052. doi: 10.1523/JNEUROSCI.6364-09.2010.
19. + exchangers. Mol. Asp. Med. 34, 236-251. doi: 10.1016/j.mam.2012.05.001.
20. Engert, F., and Bonhoeffer, T. (1999). Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66-70. doi: 10.1038/19978.
21. Forgac, M. (2007). Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 8, 917-929. doi: 10.1038/nrm2272.
22. Garcia-Regalado, A., Guzman-Hernandez, M. L., Ramirez-Rangel, I., Robles-Molina, E., Balla, T., Vazquez-Prado, J., et al. (2008). G protein-coupled receptor-promoted trafficking of Gbeta1gamma2 leads to AKT activation at endosomes via a mechanism mediated by Gbeta1gamma2-Rab11a interaction. Mol. Biol. Cell 19, 4188-4200. doi: 10.1091/mbc.E07-10-1089.
23. Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., et al. (2008). SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am. J. Hum. Genet. 82, 1003-1010. doi: 10.1016/j.ajhg.2008.01.013.
24. Gould, G. W., and Lippincott-Schwartz, J. (2009). New roles for endosomes: from vesicular carriers to multi-purpose platforms. Nat. Rev. Mol. Cell Biol. 10, 287-292. doi: 10.1038/nrm2652.
25. Greene, L. A., and Tischler, A. S. (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. U.S.A. 73, 2424-2428. doi: 10.1073/pnas.73.7.2424.
26. Gründer, S., and Chen, X. (2010). Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int. J. Physiol. Pathophysiol. Pharmacol. 2, 73.
27. Harrington, A. W., St Hillaire, C., Zweifel, L. S., Glebova, N. O., Philippidou, P., Halegoua, S., et al. (2011). Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146, 421-434. doi: 10.1016/j.cell.2011.07.008.
28. Hill, J. K., Brett, C. L., Chyou, A., Kallay, L. M., Sakaguchi, M., Rao, R., et al. (2006). Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9. J. Neurosci. 26, 9944-9955. doi: 10.1523/JNEUROSCI.2990-06.2006.
29. Hsu, K. S., Liang, Y. C., and Huang, C. C. (2000). Influence of an extracellular acidosis on excitatory synaptic transmission and long-term potentiation in the CA1 region of rat hippocampal slices. J. Neurosci. Res. 62, 403-415. doi: 10.1002/1097-4547(20001101)62:3<403::AID-JNR11>3.0.CO;2-3.
30. Huang, E. J., and Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677-736. doi: 10.1146/annurev.neuro.24.1.677.
31. Huang, S.-H., Wang, J., Sui, W.-H., Chen, B., Zhang, X.-Y., Yan, J., et al. (2013). BDNF-dependent recycling facilitates TrkB translocation to postsynaptic density during LTP via a Rab11-Dependent pathway. J. Neurosci. 33, 9214-9230. doi: 10.1523/JNEUROSCI.3256-12.2013.
32. Ihle, E. C., and Patneau, D. K. (2000). Modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization by extracellular protons. Mol. Pharmacol. 58, 1204-1212.
33. + exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons. J. Neurochem. 99, 1224-1236. doi: 10.1111/j.1471-4159.2006.04168.x.
34. Kagami, T., Chen, S., Memar, P., Choi, M., Foster, L. J., and Numata, M. (2008). Identification and biochemical characterization of the SLC9A7 interactome. Mol. Membr. Biol. 25, 436-447. doi: 10.1080/09687680802263046.
35. + exchanger stably expressed in Chinese hamster ovary cells. ATP dependence, osmotic sensitivity, and role in cell proliferation. J. Biol. Chem. 269, 23544-23552.
36. Krishek, B. J., Amato, A., Connolly, C. N., Moss, S. J., and Smart, T. G. (1996). Proton sensitivity of the GABA(A) receptor is associated with the receptor subunit composition. J. Physiol. 492 (pt 2), 431-443.
37. Kumamoto, E. (1996). Neuromodulation by Mg2+ and polyamines of excitatory amino acid currents in rodent neurones in culture. Magnes. Res. 9, 317-327.
38. Lakhan, S. E., Caro, M., and Hadzimichalis, N. (2013). NMDA receptor activity in neuropsychiatric disorders. Front. Psychiatry 4:52. doi: 10.3389/fpsyt.2013.00052.
39. Lang, C., Barco, A., Zablow, L., Kandel, E. R., Siegelbaum, S. A., and Zakharenko, S. S. (2004). Transient expansion of synaptically connected dendritic spines upon induction of hippocampal long-term potentiation. Proc. Natl. Acad. Sci. U.S.A. 101, 16665-16670. doi: 10.1073/pnas.0407581101.
40. Lasky-Su, J., Anney, R. J., Neale, B. M., Franke, B., Zhou, K., Maller, J. B., et al. (2008). Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1355-1358. doi: 10.1002/ajmg.b.30869.
41. Lazo, O. M., Gonzalez, A. S., Ascano, M., Kuruvilla, R., Couve, A. S., and Bronfman, F. C. (2013). BDNF regulates Rab11-Mediated recycling endosome dynamics to induce dendritic branching. J. Neurosci. 33, 6112-6122. doi: 10.1523/JNEUROSCI.4630-12.2013.
42. Levinthal, C., Barkdull, L., Jacobson, P., Storjohann, L., van Wagenen, B. C., Stormann, T. M., et al. (2009). Modulation of group III metabotropic glutamate receptors by hydrogen ions. Pharmacology 83, 88-94. doi: 10.1159/000180124.
43. Li, P.-A., and Siesjö, B. K. (1997). Role of hyperglycaemia-related acidosis in ischaemic brain damage. Acta Physiologica Scandinavica 161, 567-580. doi: 10.1046/j.1365-201X.1997.00264.x.
44. Lin, D. C., Quevedo, C., Brewer, N. E., Bell, A., Testa, J. R., Grimes, M. L., et al. (2006). APPL1 associates with TrkA and GIPC1 and is required for nerve growth factor-mediated signal transduction. Mol. Cell. Biol. 26, 8928-8941. doi: 10.1128/MCB.00228-06.
45. Lin, P. J., Williams, W. P., Kobiljski, J., and Numata, M. (2007). Caveolins bind to (Na+, K+)/H+ exchanger NHE7 by a novel binding module. Cell Signal. 19, 978-988. doi: 10.1016/j.cellsig.2006.11.006.
46. Liu, Y., Zaun, H. C., Orlowski, J., and Ackerman, S. L. (2013). CHP1-Mediated NHE1 biosynthetic maturation is required for purkinje cell axon homeostasis. J. Neurosci. 33, 12656-12669. doi: 10.1523/JNEUROSCI.0406-13.2013.
47. Lu, W.-Y., Man, H.-Y., Ju, W., Trimble, W. S., MacDonald, J. F., and Wang, Y. T. (2001). Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243-254. doi: 10.1016/S0896-6273(01)00194-5.
48. Malenka, R. C., and Bear, M. F. (2004). LTP and LTD: an embarrassment of riches. Neuron 44, 5-21. doi: 10.1016/j.neuron.2004.09.012.
49. Maletic-Savatic, M., Malinow, R., and Svoboda, K. (1999). Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923-1927. doi: 10.1126/science.283.5409.1923.
50. Markunas, C. A., Quinn, K. S., Collins, A. L., Garrett, M. E., Lachiewicz, A. M., Sommer, J. L., et al. (2010). Genetic variants in SLC9A9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families. Psychiatr. Genet. 20, 73-81. doi: 10.1097/YPG.0b013e3283351209.
51. Masereel, B., Pochet, L., and Laeckmann, D. (2003). An overview of inhibitors of Na+/H+ exchanger. Eur. J. Med. Chem. 38, 547-554. doi: 10.1016/S0223-5234(03)00100-4.
52. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C., and Kasai, H. (2004). Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761-766. doi: 10.1038/nature02617.
53. Maxfield, F. R., and Mcgraw, T. E. (2004). Endocytic recycling. Nat. Rev. Mol. Cell Biol. 5, 121-132. doi: 10.1038/nrm1315.
54. Meda, S. A., Narayanan, B., Liu, J., Perrone-Bizzozero, N. I., Stevens, M. C., Calhoun, V. D., et al. (2012). A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer's disease in the ADNI cohort. Neuroimage 60, 1608-1621. doi: 10.1016/j.neuroimage.2011.12.076.
55. Mick, E., Todorov, A., Smalley, S., Hu, X., Loo, S., Todd, R. D., et al. (2010). Family-based genome-wide association scan of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 49, 898-905.e3. doi: 10.1016/j.jaac.2010.02.014.
56. Mignot, C., Heron, D., Bursztyn, J., Momtchilova, M., Mayer, M., Whalen, S., et al. (2013). Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev. 35, 172-176. doi: 10.1016/j.braindev.2012.03.010.
57. Morrow, E. M., Yoo, S. Y., Flavell, S. W., Kim, T. K., Lin, Y., Hill, R. S., et al. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218-223. doi: 10.1126/science.1157657.
58. Mott, D. D., Washburn, M. S., Zhang, S., and Dingledine, R. J. (2003). Subunit-dependent modulation of kainate receptors by extracellular protons and polyamines. J. Neurosci. 23, 1179-1188.
59. Murphy, J. E., Padilla, B. E., Hasdemir, B., Cottrell, G. S., and Bunnett, N. W. (2009). Endosomes: a legitimate platform for the signaling train. Proc. Natl. Acad. Sci. U.S.A. 106, 17615-17622. doi: 10.1073/pnas.0906541106.
60. Nachshen, D. A., and Drapeau, P. (1988). The regulation of cytosolic pH in isolated presynaptic nerve terminals from rat brain. J. Gen. Physiol. 91, 289-303. doi: 10.1085/jgp.91.2.289.
61. + exchanger isoforms are distributed to golgi and post-golgi compartments and are involved in organelle pH regulation. J. Biol. Chem. 280, 1561-1572. doi: 10.1074/jbc.M410041200.
62. Nazarewicz, R. R., Salazar, G., Patrushev, N., San Martin, A., Hilenski, L., Xiong, S., et al. (2011). Early endosomal antigen 1 (EEA1) is an obligate scaffold for angiotensin II-induced, PKC-alpha-dependent Akt activation in endosomes. J. Biol. Chem. 286, 2886-2895. doi: 10.1074/jbc.M110.141499.
63. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A., and Prochiantz, A. (1984). Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462-465. doi: 10.1038/307462a0.
64. Numata, M., and Orlowski, J. (2001). Molecular cloning and characterization of a novel (Na+, K+)/H+ exchanger localized to the trans-Golgi network. J. Biol. Chem. 276, 17387-17394. doi: 10.1074/jbc.M101319200.
65. Ohgaki, R., Fukura, N., Matsushita, M., Mitsui, K., and Kanazawa, H. (2008). Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with the receptor for activated C-kinase 1. J. Biol. Chem. 283, 4417-4429. doi: 10.1074/jbc.M705146200.
66. Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., and van Ijzendoorn, S. C. (2010). The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells. Mol. Biol. Cell 21, 1293-1304. doi: 10.1091/mbc.E09-09-0767.
67. + exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50, 443-450. doi: 10.1021/bi101082e.
68. + exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells. Oncol. Rep. 27, 311-317. doi: 10.3892/or.2011.1542.
69. Orlowski, J., and Grinstein, S. (2004). Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch. 447, 549-565. doi: 10.1007/s00424-003-1110-3.
70. Orlowski, J., and Grinstein, S. (2007). Emerging roles of alkali cation/proton exchangers in organellar homeostasis. Curr. Opin. Cell Biol. 19, 483-492. doi: 10.1016/j.ceb.2007.06.001.
71. Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., et al. (2013). Christianson syndrome protein nhe6 modulates trkb endosomal signaling required for neuronal circuit development. Neuron. doi: 10.1016/j.neuron.2013.07.043.
72. Park, M., Salgado, J. M., Ostroff, L., Helton, T. D., Robinson, C. G., Harris, K. M., et al. (2006). Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817-830. doi: 10.1016/j.neuron.2006.09.040.
73. Platta, H. W., and Stenmark, H. (2011). Endocytosis and signaling. Curr. Opin. Cell Biol. 23, 393-403. doi: 10.1016/j.ceb.2011.03.008.
74. Raley-Susman, K. M., Cragoe, E. J. Jr., Sapolsky, R. M., and Kopito, R. R. (1991). Regulation of intracellular pH in cultured hippocampal neurons by an amiloride-insensitive Na+/H+ exchanger. J. Biol. Chem. 266, 2739-2745.
75. + exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions. J. Neurochem. 106, 231-243. doi: 10.1111/j.1471-4159.2008.05355.x.
76. Ronicke, R., Schroder, U. H., Bohm, K., and Reymann, K. G. (2009). The Na+/H+ exchanger modulates long-term potentiation in rat hippocampal slices. Naunyn Schmiedebergs Arch. Pharmacol. 379, 233-239. doi: 10.1007/s00210-008-0364-x.
77. + exchange system in brain synaptosomes. Brain Res. 301, 371-374. doi: 10.1016/0006-8993(84)91106-5.
78. Schenck, A., Goto-Silva, L., Collinet, C., Rhinn, M., Giner, A., Habermann, B., et al. (2008). The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 133, 486-497. doi: 10.1016/j.cell.2008.02.044.
79. Schroer, R. J., Holden, K. R., Tarpey, P. S., Matheus, M. G., Griesemer, D. A., Friez, M. J., et al. (2010). Natural history of Christianson syndrome. Am. J. Med. Genet. A 152A, 2775-2783. doi: 10.1002/ajmg.a.33093.
80. Schuchmann, S., Schmitz, D., Rivera, C., Vanhatalo, S., Salmen, B., Mackie, K., et al. (2006). Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat. Med. 12, 817-823. doi: 10.1038/nm1422.
81. 3-exchange. J. Physiol. 475, 59-67.
82. Scita, G., and Di Fiore, P. P. (2010). The endocytic matrix. Nature 463, 464-473. doi: 10.1038/nature08910.
83. Scott, C. C., and Gruenberg, J. (2011). Ion flux and the function of endosomes and lysosomes: pH is just the start: the flux of ions across endosomal membranes influences endosome function not only through regulation of the luminal pH. Bioessays 33, 103-110. doi: 10.1002/bies.201000108.
84. Shepherd, J. D., and Huganir, R. L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613-643. doi: 10.1146/annurev.cellbio.23.090506.123516.
85. Slepkov, E. R., Rainey, J. K., Sykes, B. D., and Fliegel, L. (2007). Structural and functional analysis of the Na+/H+ exchanger. Biochem. J. 401, 623-633. doi: 10.1042/BJ20061062.
86. Somjen, G. G. (1984). Acidification of interstitial fluid in hippocampal formation caused by seizures and by spreading depression. Brain Res. 311, 186-188. doi: 10.1016/0006-8993(84)91416-1.
87. Sorkin, A., and von Zastrow, M. (2009). Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol. 10, 609-622. doi: 10.1038/nrm2748.
88. Stauber, T., and Jentsch, T. J. (2013). Chloride in vesicular trafficking and function. Annu. Rev. Physiol. 75, 453-477. doi: 10.1146/annurev-physiol-030212-183702.
89. Szabo, E. Z., Numata, M., Shull, G. E., and Orlowski, J. (2000). Kinetic and pharmacological properties of human brain Na+/H+ exchanger isoform 5 stably expressed in Chinese hamster ovary cells. J. Biol. Chem. 275, 6302-6307. doi: 10.1074/jbc.275.9.6302.
90. Takahashi, Y., Hosoki, K., Matsushita, M., Funatsuka, M., Saito, K., Kanazawa, H., et al. (2011). A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 799-807. doi: 10.1002/ajmg.b.31221.
91. Tang, C. M., Dichter, M., and Morad, M. (1990). Modulation of the N-methyl-D-aspartate channel by extracellular H+. Proc. Natl. Acad. Sci. U.S.A. 87, 6445-6449. doi: 10.1073/pnas.87.16.6445.
92. Traynelis, S. F., and Cull-Candy, S. G. (1990). Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature 345, 347-350. doi: 10.1038/345347a0.
93. Trudeau, L. E., Parpura, V., and Haydon, P. G. (1999). Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification. J. Neurophysiol. 81, 2627-2635.
94. Vaegter, C. B., Jansen, P., Fjorback, A. W., Glerup, S., Skeldal, S., Kjolby, M., et al. (2011). Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat. Neurosci. 14, 54-61. doi: 10.1038/nn.2689.
95. Varsano, T., Dong, M. Q., Niesman, I., Gacula, H., Lou, X., Ma, T., et al. (2006). GIPC is recruited by APPL to peripheral TrkA endosomes and regulates TrkA trafficking and signaling. Mol. Cell Biol. 26, 8942-8952. doi: 10.1128/MCB.00305-06.
96. Velisek, L. (1998). Extracellular acidosis and high levels of carbon dioxide suppress synaptic transmission and prevent the induction of long-term potentiation in the CA1 region of rat hippocampal slices. Hippocampus 8, 24-32. doi: 10.1002/(SICI)1098-1063(1998)8:1<24::AID-HIPO3>3.0.CO;2-7.
97. Velisek, L., Dreier, J. P., Stanton, P. K., Heinemann, U., and Moshe, S. L. (1994). Lowering of extracellular pH suppresses low-Mg2+-induces seizures in combined entorhinal cortex-hippocampal slices. Exp. Brain Res. 101, 44-52. doi: 10.1007/BF00243215.
98. Wakabayashi, S., Shigekawa, M., and Pouyssegur, J. (1997). Molecular physiology of vertebrate Na+/H+ exchangers. Physiol. Rev. 77, 51-74.
99. Walz, H. A., Shi, X., Chouinard, M., Bue, C. A., Navaroli, D. M., Hayakawa, A., et al. (2010). Isoform-specific regulation of Akt signaling by the endosomal protein WDFY2. J. Biol. Chem. 285, 14101-14108. doi: 10.1074/jbc.M110.110536.
100. Wang, Z., Edwards, J. G., Riley, N., Provance, D. W. Jr., Karcher, R., Li, X. D., et al. (2008). Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135, 535-548. doi: 10.1016/j.cell.2008.09.057.
101. Wemmie, J. A., Zha, X.-M., and Welsh, M. J. (2008). "Acid-sensing ion channels (ASICs) and pH in synapse physiology," in Structural and Functional Organization of the Synapse, eds J. W. Hell and M. D. Ehlers (Philadelphia, PA: Springer), 661-681.
102. Xinhan, L., Matsushita, M., Numaza, M., Taguchi, A., Mitsui, K., and Kanazawa, H. (2011). Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am. J. Physiol. Cell Physiol. 301, C1431-C1444. doi: 10.1152/ajpcell.00154.2011.
103. Zha, X. M. (2013). Acid-sensing ion channels: trafficking and synaptic function. Mol. Brain 6, 1. doi: 10.1186/1756-6606-6-1.
104. Zha, X. M., Wemmie, J. A., Green, S. H., and Welsh, M. J. (2006). Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines. Proc. Natl. Acad. Sci. U.S.A. 103, 16556-16561. doi: 10.1073/pnas.0608018103.
105. Zhou, Q., and Sheng, M. (2013). NMDA receptors in nervous system diseases. Neuropharmacology 74, 69-75. doi: 10.1016/j.neuropharm.2013.03.030.