Abstract
Neuronal ion channels of different types often do not function independently but will inhibit or potentiate the activity of other types of channels, a process called cross-talk. The N-methyl-D-aspartate receptor (NMDA receptor) and the γ-aminobutyric acid type A receptor (GABAA receptor) are important excitatory and inhibitory receptors in the central nervous system, respectively. Currently, cross-talk between the NMDA receptor and the GABAA receptor, particularly in the central auditory system, is not well understood. In the present study, we investigated functional interactions between the NMDA receptor and the GABAA receptor using whole-cell patch-clamp techniques in cultured neurons from the inferior colliculus, which is an important nucleus in the central auditory system. We found that the currents induced by aspartate at 100 μmol L−1 were suppressed by the pre-perfusion of GABA at 100 μmol L−1, indicating cross-inhibition of NMDA receptors by activation of GABAA receptors. Moreover, we found that the currents induced by GABA at 100 μmol L−1 (IGABA) were not suppressed by the pre-perfusion of 100 μmol L−1 aspartate, but those induced by GABA at 3 μmol L−1 were suppressed, indicating concentration-dependent cross-inhibition of GABAA receptors by activation of NMDA receptors. In addition, inhibition of IGABA by aspartate was not affected by blockade of voltage-dependent Ca2+ channels with CdCl2 in a solution that contained Ca2+, however, CdCl2 effectively attenuated the inhibition of IGABA by aspartate when it was perfused in a solution that contained Ba2+ instead of Ca2+ or a solution that contained Ca2+ and 10 mmol L−1 BAPTA, a membrane-permeable Ca2+ chelator, suggesting that this inhibition is mediated by Ca2+ influx through NMDA receptors, rather than voltage-dependent Ca2+ channels. Finally, KN-62, a potent inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), reduced the inhibition of IGABA by aspartate, indicating the involvement of CaMKII in this cross-inhibition. Our study demonstrates a functional interaction between NMDA and GABAA receptors in the inferior colliculus of rats. The presence of cross-talk between these receptors suggests that the mechanisms underlying information processing in the central auditory system may be more complex than previously believed.
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References
Nakazawa K, Inoue K, Koizumi S. Facilitation by 5-hydroxytryptamine of ATP-activated current in rat pheochromocytoma cells. Pflugers Arch, 1994, 427: 492–499 7526334, 10.1007/BF00374266, 1:CAS:528:DyaK2cXlt1Grsbk%3D
Xu T L, Li J S, Jin Y H, et al. Modulation of the glycine response by Ca -permeable AMPA receptors in rat spinal neurones. J Physiol, 1999, 514(Pt 3): 701–711 9882741, 10.1111/j.1469-7793.1999.701ad.x, 1:CAS:528:DyaK1MXhsl2lur0%3D
Lee F J, Xue S, Pei L, et al. Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell, 2002, 111: 219–230 12408866, 10.1016/S0092-8674(02)00962-5, 1:CAS:528:DC%2BD38Xotlahsro%3D
Li Y, Wu L J, Legendre P, et al. Asymmetric cross-inhibition between GABAA and glycine receptors in rat spinal dorsal horn neurons. J Biol Chem, 2003, 278: 38637–38645 12885784, 10.1074/jbc.M303735200, 1:CAS:528:DC%2BD3sXnslWjsrY%3D
Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci, 1994, 17: 31–108 8210177, 10.1146/annurev.ne.17.030194.000335, 1:CAS:528:DyaK2cXitVyltrs%3D
Seeburg P H. The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci, 1993, 16: 359–365 7694406, 10.1016/0166-2236(93)90093-2, 1:CAS:528:DyaK3sXmtFOnu7o%3D
Harvey R J, Depner U B, Wassle H, et al. GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science, 2004, 304: 884–887 15131310, 10.1126/science.1094925, 1:CAS:528:DC%2BD2cXjs1KjtLs%3D
Ahmadi S, Lippross S, Neuhuber W L, et al. PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci, 2002, 5: 34–40 11740501, 10.1038/nn778, 1:CAS:528:DC%2BD38XjtlCquw%3D%3D
Casseday J H, Ehrlich D, Covey E. Neural tuning for sound duration: role of inhibitory mechanisms in the inferior colliculus. Science, 1994, 264: 847–850 8171341, 10.1126/science.8171341, 1:STN:280:DyaK2c3isFagsg%3D%3D
Brand A, Behrend O, Marquardt T, et al. Precise inhibition is essential for microsecond interaural time difference coding. Nature, 2002, 417: 543–547 12037566, 10.1038/417543a, 1:CAS:528:DC%2BD38XktVehtL0%3D
Stephenson F A. The GABAA receptors. Biochem J, 1995, 310(Pt 1): 1–9 7646429, 1:CAS:528:DyaK2MXnsVyjtLk%3D
Betz H. Glycine receptors: heterogeneous and widespread in the mammalian brain. Trends Neurosci, 1991, 14: 458–461 1722365, 10.1016/0166-2236(91)90045-V, 1:CAS:528:DyaK38XnsVE%3D
Adams J C, Wenthold R J. Distribution of putative amino acid transmitters, choline acetyltransferase and glutamate decarboxylase in the inferior colliculus. Neuroscience, 1979, 4: 1947–1951 231219, 10.1016/0306-4522(79)90067-8, 1:CAS:528:DyaL3cXptFGkug%3D%3D
Ma C L, Kelly J B, Wu S H. AMPA and NMDA receptors mediate synaptic excitation in the rat’s inferior colliculus. Hear Res, 2002, 168: 25–34 12117506, 10.1016/S0378-5955(02)00370-2, 1:CAS:528:DC%2BD38XltFWjtbw%3D
Chen Q X, Wong R K. Suppression of GABAA receptor responses by NMDA application in hippocampal neurones acutely isolated from the adult guinea-pig. J Physiol, 1995, 482(Pt 2): 353–362 7714826, 1:CAS:528:DyaK2MXjslanu7k%3D
Robello M, Amico C, Cupello A. A dual mechanism for impairment of GABAA receptor activity by NMDA receptor activation in rat cerebellum granule cells. Eur Biophys J, 1997, 25: 181–187 9037753, 10.1007/s002490050030, 1:CAS:528:DyaK2sXhvVehtL0%3D
Wang D, Lu H, Xu T. Mediation by calcium/calmodulin-dependent protein kinase II of suppression of GABA(A) receptors by NMDA. Sci China C-Life Sci, 2000, 43: 655–662 18726361, 10.1007/BF02882287, 1:CAS:528:DC%2BD3MXkt1Gjsbc%3D
Tang Z Q, Lu Y G, Zhou K Q, et al. Amiloride attenuates glycine-induced currents in cultured neurons of rat inferior colliculus. Biochem Biophys Res Commun, 2006, 350: 900–904 17034762, 10.1016/j.bbrc.2006.09.110, 1:CAS:528:DC%2BD28XhtFSrtL%2FM
Murase K, Ryu P D, Randic M. Excitatory and inhibitory amino acids and peptide-induced responses in acutely isolated rat spinal dorsal horn neurons. Neurosci Lett, 1989, 103: 56–63 2476693, 10.1016/0304-3940(89)90485-0, 1:CAS:528:DyaL1MXltV2mtLk%3D
Mouginot D, Feltz P, Schlichter R. Modulation of GABA-gated chloride currents by intracellular Ca2+ in cultured porcine melanotrophs. J Physiol, 1991, 437: 109–132 1653849, 1:CAS:528:DyaK3MXisVWitrY%3D
Martina M, Kilic G, Cherubini E. The effect of intracellular Ca2+ on GABA-activated currents in cerebellar granule cells in culture. J Membr Biol, 1994, 142: 209–216 7884812, 10.1007/BF00234942, 1:CAS:528:DyaK2MXit1Gru70%3D
Stelzer A, Shi H. Impairment of GABAA receptor function by N-methyl-D-aspartate-mediated calcium influx in isolated CA1 pyramidal cells. Neuroscience, 1994, 62: 813–828 7870309, 10.1016/0306-4522(94)90479-0, 1:CAS:528:DyaK2cXmsVKqu78%3D
Xu J, Liu Y, Zhang G Y. Neuroprotection of GluR5-containing kainate receptor activation against ischemic brain injury through decreasing tyrosine phosphorylation of N-methyl-D-aspartate receptors mediated by Src kinase. J Biol Chem, 2008, 283: 29355–29366 18678878, 10.1074/jbc.M800393200, 1:CAS:528:DC%2BD1cXht1GlsbrL
Mulle C, Choquet D, Korn H, et al. Calcium influx through nicotinic receptor in rat central neurons: its relevance to cellular regulation. Neuron, 1992, 8: 135–143 1309647, 10.1016/0896-6273(92)90115-T, 1:CAS:528:DyaK38Xht1WlsLc%3D
Ghosh A, Greenberg M E. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science, 1995, 268: 239–247 7716515, 10.1126/science.7716515, 1:CAS:528:DyaK2MXltVCitLY%3D
Pitler T A, Alger B E. Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J Neurosci, 1992, 12: 4122–4132 1403103, 1:CAS:528:DyaK38Xmt1Krtbk%3D
Chen Q X, Stelzer A, Kay A R, et al. GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea-pig hippocampal neurones. J Physiol, 1990, 420: 207221
Braun A P, Schulman H. The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol, 1995, 57: 417–445 7778873, 10.1146/annurev.ph.57.030195.002221, 1:CAS:528:DyaK2MXksVeqsL0%3D
McDonald B J, Moss S J. Differential phosphorylation of intracellular domains of gamma-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. J Biol Chem, 1994, 269: 18111–18117 8027073, 1:CAS:528:DyaK2cXkslCnsrs%3D
Xu T L, Dong X P, Wang D S. N-methyl-D-aspartate enhancement of the glycine response in the rat sacral dorsal commissural neurons. Eur J Neurosci, 2000, 12: 1647–1653 10792442, 10.1046/j.1460-9568.2000.00065.x, 1:STN:280:DC%2BD3c3lt12hsA%3D%3D
Liu F, Wan Q, Pristupa Z B, et al. Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors. Nature, 2000, 403: 274–280 10659839, 10.1038/35001232, 1:CAS:528:DC%2BD3cXns1Cisw%3D%3D
Obrietan K, van den Pol A N. GABA neurotransmission in the hypothalamus: developmental reversal from Ca2+ elevating to depressing. J Neurosci, 1995, 15: 5065–5077 7623135, 1:CAS:528:DyaK2MXmvFygur4%3D
Takebayashi M, Kagaya A, Hayashi T, et al. gamma-Aminobutyric acid increases intracellular Ca2+ concentration in cultured cortical neurons: role of Cl-transport. Eur J Pharmacol, 1996, 297: 137–143 8851177, 10.1016/0014-2999(95)00734-2, 1:CAS:528:DyaK28Xht1WltLo%3D
Wu S H, Ma C L, Kelly J B. Contribution of AMPA, NMDA, and GABA(A) receptors to temporal pattern of postsynaptic responses in the inferior colliculus of the rat. J Neurosci, 2004, 24: 4625–4634 15140934, 10.1523/JNEUROSCI.0318-04.2004, 1:CAS:528:DC%2BD2cXksFCquro%3D
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Cong, D., Tang, Z., Li, L. et al. Cross-talk between NMDA and GABAA receptors in cultured neurons of the rat inferior colliculus. Sci. China Life Sci. 54, 560–566 (2011). https://doi.org/10.1007/s11427-011-4178-6
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DOI: https://doi.org/10.1007/s11427-011-4178-6