The Role of Calcium-Dependent Desensitization in the Potentiation by GNE-9278 of NMDA Receptor Currents in Rat Cortal Neurons in vitro

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Аннотация

To compensate for the lack of functions of NMDA receptors in the central nervous system against the background of dementia, positive allosteric modulators (PAMs) are of great interest. Known PAMs increase the amplitude of integral ion currents carried by NMDA receptors, but do not affect the calcium-calmodulin dependent desensitization of the latter. We studied the possibility of modulating NMDA receptor desensitization by the newly synthesized PAM GNE-9278, which has a unique binding site on the transmembrane domain. Experiments were performed on native NMDA receptors expressed in rat neocortical neurons in primary tissue culture. Using the “patch-clamp” method of recording transmembrane currents, a comparative study of the effect of three substances potentiating NMDA receptor currents on the desensitization of these receptors was carried out: GNE-9278 (10 µM), dithiothreitol (1 mM) and copper ions (5 µM). These substances increased the amplitude of currents evoked by 100 μM NMDA, but only GNE-9278 reduced the difference between steady-state and peak current amplitudes by 15%. In addition, GNE-9278 doubled the decay time constant from peak to steady state, i.e., weakened the desensitization of NMDA receptors. Because GNE-9278 did not alter the effective extracellular calcium concentration to generate desensitization, its effect likely does not affect the receptor's interaction with calmodulin. Analysis of the shape of the currents within the framework of the kinetic model revealed that GNE-9278 reduces two kinetic parameters: the rate of channel closure, which determines the time of the open state, as well as the rates of entry into and exit of the receptor from the desensitized state, which determine the probability of the open state of the channel. Modulation of calcium-dependent NMDA receptor desensitization distinguishes GNE-9278 from other known PAMs, which is likely determined by the binding site of GNE-9278 in the pre-M1 domain of the GluN1 subunit.

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Авторлар туралы

A. Fedorina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: dsibarov@gmail.com
Ресей, Saint Petersburg

S. Antonov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: dsibarov@gmail.com
Ресей, Saint Petersburg

D. Sibarov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: dsibarov@gmail.com
Ресей, Saint Petersburg

Әдебиет тізімі

  1. Hansen KB, Wollmuth LP, Bowie D, Furukawa H, Menniti FS, Sobolevsky AI, Swanson GT, Swanger SA, Greger IH, Nakagawa T, McBain CJ, Jayaraman V, Low CM, Dell'Acqua ML, Diamond JS, Camp CR, Perszyk RE, Yuan H, Traynelis SF (2015) Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacol Rev 73(4): 298–487. https://doi.org/10.1124/pharmrev.120.000131
  2. Ehlers MD, Zhang S, Bernhadt JP, Huganir RL (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84: 745–755. https://doi.org/10.1016/s0092-8674(00)81052-1
  3. Sibarov DA, Antonov SM (2018) Calcium-dependent desensitization of NMDA receptors. Biochemistry (Moscow) 83(10): 1173–1183. https://doi.org/10.1134/S0006297918100036
  4. Sibarov DA, Abushik PA, Poguzhelskaya EE, Bolshakov KV, Antonov SM (2015) Inhibition of plasma membrane Na/Ca-exchanger by KB-R7943 or lithium reveals its role in Ca-dependent N-methyl-D-aspartate receptor inactivation. J Pharmacol Exp Ther 355(3): 484–495. https://doi.org/10.1124/jpet.115.227173
  5. Boikov SI, Karelina TV, Sibarov DA, Antonov SM (2024) Selective inhibitor of sodium-calcium exchanger, SEA0400, affects NMDA receptor currents and abolishes their calcium-dependent block by tricyclic antidepressants. Front Pharmacol 15:1432718. https://doi.org/10.3389/fphar.2024.1432718
  6. Rycroft BK, Gibb AJ (2004) Regulation of single NMDA receptor channel activity by alpha-actinin and calmodulin in rat hippocampal granule cells. J Physiol 557(3): 795–808. https://doi.org/10.1113/jphysiol.2003.059212
  7. Zhang S, Ehlers MD, Bernhardt JP, Su CT, Huganir RL (1998) Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors. Neuron 21(2): 443–453.
  8. Krupp JJ, Vissel B, Heinemann SF, Westbrook GL (1996) Calcium-dependent inactivation of recombinant N-methyl-D-aspartate receptors is NR2 subunit specific. Mol Pharmacol 50(6): 1680–1688.
  9. Hill MD, Blanco M, Salituro FG, Bai Z, Beckley JT, Ackley MA, Dai J, Doherty JJ, Harrison BL, Hoffmann EC, Kazdoba TM, Lanzetta D, Lewis M, Quirk MC, Robichaud AJ (2022) SAGE-718: A first-in-class N-methyl-D-aspartate receptor positive allosteric modulator for the potential treatment of cognitive impairment. J Med Chem 65(13): 9063–9075. https://doi.org/10.1021/acs.jmedchem.2c00313
  10. Rock DM, Macdonald RL (1995) Polyamine regulation of N-methyl-D-aspartate receptor channels. Annu Rev Pharmacol Toxicol 35: 463–482. https://doi.org/10.1146/annurev.pa.35.040195.002335
  11. Skatchkov SN, Antonov SM, Eaton MJ (2016) Glia and glial polyamines. Role in brain function in health and disease. Biochem (Mosc) Suppl Ser A Membr Cell Biol 10: 73–98. https://doi.org/10.1134/S1990747816010116
  12. Bowlby MR (1993) Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons. Mol Pharmacol 43: 813e819.
  13. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu HJ, Izumi Y, Mennerick SJ (2013) The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci 33: 17290−17300. https://doi.org/10.1523/JNEUROSCI.2619-13.2013
  14. Skeberdis VA, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, Lin Y, Bennett MV, Yuste R, Castillo PE, Zukin RS (2006) Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci 9(4): 501–510. https://doi.org/10.1038/nn1664
  15. Jackson MF, Konarski JZ, Weerapura M, Czerwinski W, MacDonald JF (2006) Protein kinase C enhances glycine-insensitive desensitization of NMDA receptors independently of previously identified protein kinase C sites. J Neurochem 96(6): 1509–1518. https://doi.org/10.1111/j.1471-4159.2006.03651.x
  16. Köhr G, Eckardt S, Lüddens H, Monyer H, Seeburg PH (1994) NMDA receptor channels: Subunit-specific potentiation by reducing agents. Neuron 12: 1031–1040. https://doi.org/10.1016/0896-6273(94)90311-5
  17. Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16: 1066–1071. https://doi.org/10.1523/JNEUROSCI.16-03-01066.1996
  18. Marchetti C, Baranowska-Bosiacka I, Gavazzo P (2014) Multiple effects of copper on NMDA receptor currents. Brain Res 1542: 20–31. https://doi.org/10.1016/j.brainres.2013.10.029
  19. Sibarov DA, Boikov SI, Karelina TV, Antonov SM (2020) GluN2 Subunit-dependent redox modulation of NMDA receptor activation by homocysteine. Biomolecules 10: 1441. https://doi.org/10.3390/biom10101441
  20. Zhang XL, Li YX, Berglund N, Burgdorf JS, Donello JE, Moskal JR, Stanton PK (2024) Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-D-aspartate receptors. Neuropharmacology 6; 259:110100. https://doi.org/10.1016/j.neuropharm.2024.110100.
  21. Yakovlev AV, Kurmasheva E, Ishchenko Y, Giniatullin R, Sitdikova G (2017) Age-dependent, subunit specific action of hydrogen sulfide on GluN1/2A and GluN1/2B NMDA receptors. Front Cell Neurosci 11: 375. https://doi.org/10.3389/FNCEL.2017.00375
  22. Chen CQ, Xin H, Zhu YZ (2007) Hydrogen sulfide: third gaseous transmitter, but with great pharmacological potential. Acta Pharmacol Sin. 28(11): 1709–1716. https://doi.org/10.1111/j.1745-7254.2007.00629.x. PMID: 17959020.
  23. Varga V, Jenei Z, Janáky R, Saransaari P, Oja SS (1997) Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Neurochem Res 22(9): 1165–1171. https://doi.org/10.1023/a:1027377605054. PMID: 9251108.
  24. Horak M, Vlcek K, Petrovic M, Chodounska H, Vyklicky LJr (2004) Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors. J Neurosci 24(46): 10318–10325. https://doi.org/10.1523/JNEUROSCI.2099–04.2004
  25. Wang TM, Brown BM, Deng L, Sellers BD, Lupardus PJ, Wallweber HJA, Gustafson A, Wong E, Volgraf M, Schwarz JB, Hackos DH, Hanson JE (2017) A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain. Neuropharmacology, 121: 204–218. https://doi.org/10.1016/j.neuropharm.2017.04.041
  26. Bhatia NK, Carrillo E, Durham RJ, Berka V, Jayaraman V (2020) Allosteric changes in the NMDA receptor associated with calcium-dependent inactivation. Biophys J 119(11): 2349–2359. https://doi.org/10.1016/j.bpj.2020.08.045.
  27. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12: 529–540. https://doi.org/10.1016/ 0896-6273(94)90210-0
  28. Paoletti P, Bellone C, Zhou Q (2013) NMDA Receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14: 383–400. https://doi.org/10.1038/nrn3504
  29. Mironova EV, Evstratova AA, Antonov SM (2007) A fluorescence vital assay for the recognition and quantification of excitotoxic cell death by necrosis and apoptosis using confocal microscopy on neurons in culture. J Neurosci Meth 163(1): 1–8. https://doi.org/10.1016/j.jneumeth.2007.02.010
  30. Lester RA, Jahr CE (1992) NMDA channel behavior depends on agonist affinity. J Neurosci 12(2): 635–643. https://doi.org/10.1523/JNEUROSCI.12–02–00635.1992
  31. Sullivan JM, Traynelis SF, Chen HS, Escobar W, Heinemann SF, Lipton SA (1994) Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Neuron 13(4): 929-936. https://doi.org/10.1016/0896-6273(94)90258-5.
  32. Jang MK, Mierke DF, Russek SJ, Farb DH (2004) A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity. Proc Natl Acad Sci U S A 101(21): 8198–8203. https://doi.org/10.1073/pnas.0401838101
  33. Ogden KK, Traynelis SF (2013) Contribution of the M1 transmembrane helix and pre-M1 regionto positive allosteric modulation and gating of N-methyl-D-aspartate receptors. Mol pharmacol 83(5): 1045–1056. https://doi.org/10.1124/mol.113.085209

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2. Fig. 1. Effect of positive allosteric modulators on the degree of calcium-dependent desensitisation of NMDA receptors

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3. Fig. 2. Effect of positive allosteric modulators on peak current induced by application of 100 μM NMDA in the presence of 30 μM glycine under different experimental conditions

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4. Fig. 3. Quantitative dependence of the effect of GNE-9278 on the severity of calcium-dependent desensitisation of NMDA receptors on the concentration of extracellular calcium

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5. Fig. 4. Analysis of the possible mechanism of action of GNE-9278 within the framework of the NMDA receptor kinetic model

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