Copper Ions Reduce the Effect of Protons on Desensitization of Glycine Receptors
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 6, October, 2020 PHARMACOLOGY AND TOXICOLOGY
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Copper Ions Reduce the Effect of Protons on Desensitization of Glycine Receptors E. I. Solntseva, J. V. Bukanova, R. V. Kondratenko, and V. G. Skrebitsky
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 6, pp. 736-740, June, 2020 Original article submitted March 2, 2020 Chloride current (IGly) evoked by the rapid (600 msec) application of glycine on isolated pyramidal neurons of the rat hippocampus was recorded using the patch clamp technique. We studied the effect of individual or combined application of copper ions (Cu2+) and protons (H+) on IGly. It was found that both Cu2+ (10 μM) and H+ (pH 7.0 and 6.0) applied separately caused a fast and reversible effect on IGly that included two components: a decrease in peak amplitude (Ipeak) and a decrease in the desensitization time constant (τdes). During combined application, the effects on Ipeak were additive, which indicates the independence of the mechanisms of these effects. At the same time, the effect of combined application of Cu2+ and H+ on τdes was not additive and sometimes a slowdown of the total desensitization was observed. The latter result suggests that H+ and Cu2+ can play the role of mutual antagonists when they affect the desensitization of GlyR. Key Words: glycine receptor; copper ions; protons; hippocampus Glycine receptors (GlyRs) are one of the main components of the hippocampal inhibitory system. Activation of GlyR with glycine is followed by opening of chloride channel of the receptor and chloride ions entry into the cell, which leads to hyperpolarization of the membrane and inhibition of spike activity. Glycine-induced chloride current (IGly) is regulated by various endogenous and exogenous molecules, such as neurosteroids, alcohol, peptides, anesthetics, etc. [14,15]. IGly can also be regulated by various cations [9,14], among which protons and copper ions attract particular attention. In CNS, the concentration of copper ions (Cu2+) in the extracellular space varies in the range 0.2-1.7 μM and can reach 200 μM in the synaptic cleft [10]. Copper ions can modulate synaptic transmission and neuronal excitability [5,6] and contribute to the mechanisms of psychiatric diseases [12]. GlyRs are an important target for copper ions. The inhibitory effect of Cu2+ on IGly with IC50=71 μM was shown in recombinant GlyR expressed in HEK293 cells [3]. Research Center of Neurology, Moscow, Russia. Address for corre spondence: [email protected]. E. I. Solntseva
The decrease in pH with a corresponding increase in the content of protons (H+) in CNS is observed under physiological and pathophysiological conditions [11]. Local pH shifts, for example, in the synaptic cleft, can reach significant values up to pH 6.0 and even lower [11]. It is known that protons interact with various proteins and modulate their activity. In our study [2], as well as in the works of other authors [13], the inhibitory effect of protons on
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