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Mechanisms of H + Modulation of Glycinergic Response in Rat Sacral Dorsal Commissural Neurons
Author(s) -
Li YanFang,
Wu LongJun,
Li Yong,
Xu Lin,
Xu TianLe
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.047324
Subject(s) - commissure , glycine receptor , dorsum , neuroscience , electrophysiology , glycine , modulation (music) , biology , chemistry , anatomy , physics , biochemistry , amino acid , acoustics
Many ionotropic receptors are modulated by extracellular H + . So far, few studies have directly addressed the role of such modulation at synapses. In the present study, we investigated the effects of changes in extracellular pH on glycinergic miniature inhibitory postsynaptic currents (mIPSCs) as well as glycine‐evoked currents ( I Gly ) in mechanically dissociated spinal neurons with native synaptic boutons preserved. H + modulated both the mIPSCs and I Gly biphasically, although it activated an amiloride‐sensitive inward current by itself. Decreasing extracellular pH reversibly inhibited the amplitude of the mIPSCs and I Gly , while increasing external pH reversibly potentiated these parameters. Blockade of acid‐sensing ion channels (ASICs) with amiloride, the selective antagonist of ASICs, or decreasing intracellular pH did not alter the modulatory effect of H + on either mIPSCs or I Gly . H + shifted the EC 50 of the glycine concentration‐response curve from 49.3 ± 5.7 μ m at external pH 7.4 to 131.5 ± 8.1 μM at pH 5.5, without altering the Cl − selectivity of the glycine receptor (GlyR), the Hill coefficient and the maximal I Gly , suggesting a competitive inhibition of I Gly by H + . Both Zn 2+ and H + inhibited I Gly . However, H + induced no further inhibition of I Gly in the presence of a saturating concentration of Zn 2+ . In addition, H + significantly affected the kinetics of glycinergic mIPSCs and I Gly . It is proposed that H + and/or Zn 2+ compete with glycine binding and inhibit the amplitude of glycinergic mIPSCs and I Gly . Moreover, binding of H + induces a global conformational change in GlyR, which closes the GlyR Cl − channel and results in the acceleration of the seeming desensitization of I Gly as well as speeding up the decay time constant of glycinergic mIPSCs. However, the deprotonation rate is faster than the unbinding rate of glycine from the GlyR, leading to reactivation of the undesensitized GlyR after washout of agonist and the appearance of a rebound I Gly . H + also modulated the glycine cotransmitter, GABA‐activated current ( I GABA ). Taken together, the results support a ‘conformational coupling’ model for H + modulation of the GlyR and suggest that H + may act as a novel modulator for inhibitory neurotransmission in the mammalian spinal cord.