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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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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Sobre autores

A. Fedorina

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

Email: dsibarov@gmail.com
Rússia, Saint Petersburg

S. Antonov

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

Email: dsibarov@gmail.com
Rússia, Saint Petersburg

D. Sibarov

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

Autor responsável pela correspondência
Email: dsibarov@gmail.com
Rússia, Saint Petersburg

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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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