The hyperpolarization of spinal motoneurones by glycine and related amino acids

Curtis, D. R.; Hösli, L.; Johnston, Graham A.R.; Johnston, Ian

doi:10.1007/bf00238666

Cited by 463 publications

(102 citation statements)

References 37 publications

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“…Therefore, PMBA, an w-phosphono-x-amino acid, would be expected to reduce depolarizing responses to NMDA. However PMBA (100 jiM) did not affect the depolarization induced by NMDA (10-501iM) (Curtis et al, 1968b). In newborn rats, however, glycine causes depolarizing responses (Yanagisawa et al, 1982), which is probably due to the difference of the equilibrium potential of chloride ions (Takahashi, 1984), and responses to GABA also very closely resemble those to glycine.…”

Section: Electrophysiological Studies In Isolated Spinal Cordsmentioning

confidence: 86%

“…In newborn rats, however, glycine causes depolarizing responses (Yanagisawa et al, 1982), which is probably due to the difference of the equilibrium potential of chloride ions (Takahashi, 1984), and responses to GABA also very closely resemble those to glycine. Glycine (100 jiM-1 mM) and other agonists such as L-z-alanine, L-serine, P-alanine, taurine and D-M-alanine (Curtis et al, 1968b, Aprison, 1990) caused dose-dependent depolarization of motoneurones in newborn rats, although the depolarizing activities of these glycine agonists were considerably less than that of glycine itself on a molar basis. The rank order of their depolarizing activities in the motoneurones was as follows: glycine (1)> 13-alanine (0.85) were 8 ± 2 tiM, 9 ± 3 tiM and 0.08 ± 0.04 jtM, respectively (n = 5).…”

Section: Electrophysiological Studies In Isolated Spinal Cordsmentioning

confidence: 99%

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A novel antagonist, phenylbenzene ω‐phosphono‐α‐amino acid, for strychnine‐sensitive glycine receptors in the rat spinal cord

Saitoh

Ishida

Maruyama

et al. 1994

British J Pharmacology

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1 3-[2'-Phosphonomethyl[1,1'-biphenyl]-3-yl]alanine (PMBA) is a novel glycine antagonist at strychnine-sensitive receptors. The chemical structure of PMBA, possessing both a glycine moiety and a phosphono group, is quite different from that of strychnine.2 In the spinal motoneurone of newborn rats, glycine (100 gmM-1 mM) induced depolarizing responses in a concentration-dependent manner. PMBA effectively inhibited depolarizing responses to glycine and other agonists, such as taurine and P-alanine. The dose-response curves for glycine were shifted to the right in an almost parallel manner (pA2 value: 5.30 ± 0.23, n = 5) by PMBA which was about 60 times less potent than strychnine (pA2 value: 7.08 ± 0.21, n = 5) as a glycine antagonist. 3 PMBA (1-100 1AM) did not interact with modulatory glycine sites on N-methyl-D-aspartate (NMDA) receptors, which suggests a high selectivity of PMBA for strychnine-sensitive glycine receptors. At considerably high concentrations (0.1 mM-I mM), PMBA depressed responses to GABA (pA2 value: 3.57±0.24, n=3). 4 PMBA inhibited the binding of [3H]-strychnine to synaptosomes from adult rat spinal cords; the IC50 values of PMBA, glycine and strychnine were 8 ± 2, 9 + 3 and 0.08 ± 0.04 JM, respectively (n = 5) for[3H]-strychnine (4.8 nM). 5 PMBA is a central excitant drug with relatively high potency and selectivity and should be useful as a pharmacological probe for analysing the mechanisms underlying physiological functions of glycine receptors.

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Section: Electrophysiological Studies In Isolated Spinal Cordsmentioning

confidence: 86%

Section: Electrophysiological Studies In Isolated Spinal Cordsmentioning

confidence: 99%

A novel antagonist, phenylbenzene ω‐phosphono‐α‐amino acid, for strychnine‐sensitive glycine receptors in the rat spinal cord

Saitoh

Ishida

Maruyama

et al. 1994

British J Pharmacology

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“…Indeed glycine may be a more potent depressant of spinal motoneurones than GABA (Curtis, Hosli & Johnston, 1968;Curtis et al, 1968b). Similarly, Hosli, Tebecis & Filias (1969) found brain stem neurones lying deep to the cuneate nucleus to resemble motoneurones and suggested that glycine may be the inhibitory transmitter of medullary reticular neurones.…”

Section: Discussionmentioning

confidence: 99%

On the pharmacology of the γ‐aminobutyric acid receptors on the cuneo‐thalamic relay cells of the cat

Kelly

Renaud

1973

British J Pharmacology

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Summary1. y-Aminobutyric acid (GABA) and glycine applied by iontophoresis were equipotent depressants of cuneo-thalamic relay neurones isolated from the middle third of the cuneate nucleus of cats either decerebrated or anaesthetized with sodium pentobarbitone. 2. Glycine 13+2 nA and GABA 20+2 nA were equipotent depressors of hair cells (n=22) and, bicuculline applied by iontophoresis caused a parallel shift to the right of the GABA but not the glycine log-current response curves. The GABA equipotent dose-ratio was 20 + 0-2 for bicuculline currents of approximately 144 nA lasting about 11 min in cells excited either transynaptically by peripheral stimulation or postsynaptically by glutamate. 3. Although a maximal bicuculline current seldom caused a significant shift of the glycine-log current response curve, many of our records show the onset of the glycine response to be slowed by doses in excess of 84 nA.4. Bicuculline also antagonized depressions by fl-guanidinopropionic acid, and 8-aminovaleric acid which mimicked the action of GABA. 5. When tested on the same neurone, bicuculline and picrotoxin applied by iontophoresis were equipotent and their effects appear to be additive. 6. The GABA sensitivity was not modified by repetitive (5 or 6) doses of i.v. bicuculline (0-2 mg/kg). 7. The antagonism of GABA by bicuculline and picrotoxin appears to be of sufficient specificity to enable the separate roles of GABA and glycine as putative inhibitory transmitters of cuneo-thalamic relav cells to be determined.

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“…Inhibitory glycinergic neurotransmission is antagonized by the convulsive alkaloid strychnine (8). Young and Snyder (9,10) showed that [3H]strychnine could bind with high affinity (Kd = 2-12 nM) (9,11) to membranes from rat spinal cord.…”

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confidence: 99%

Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.

Vandenberg

French

Barry

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. Glycine activation of the receptor is antagonized by the convulsant alkaloid strychnine. Using in vitro mutagenesis and functional analysis of the cDNA encoding the al subunit of the human GlyR, we have identified several amino acid residues that form the strychnine-binding site. These residues were identified by transient expression of mutated cDNAs in mammalian (293) cells and examination of resultant [3H]strychnine binding, glycine displacement of [3Hlstrychnine, and electrophysiological responses to the application of glycine and strychnine. This mutational analysis revealed that residues from two separate domains within the al subunit form the binding site for the antagonist strychnine. The first domain includes the amino acid residues Gly-160 and Tyr-161, and the second domain includes the residues Lys-200 and Tyr-202. These results, combined with analyses of other ligand-gated ion channel receptors, suggest a conserved tertiary structure and a common mechanism for antagonism in this receptor superfamily.The inhibitory action of glycine in the spinal cord and brain stem is generated through activation of the glycine receptor (GlyR), with subsequent opening of the integral chloride channel. The GlyR complex, isolated from rat spinal cord, consists of two distinct subunits with apparent molecular masses of 48 kDa (a) and 58 kDa (J3), which associate to form a pentameric structure (for review, see ref. 1). Rat and human cDNAs encoding three different receptor a subunit subtypes and a, subunit have been cloned and sequenced (2-5). The predicted amino acid sequences and hydrophobicity profiles of these subunits are markedly similar to those of the y-aminobutyric acid type A receptor (GABAAR) subunits and also with the nicotinic acetylcholine receptor (nAChR) subunits, thus defining the ligand-gated ion channel receptor superfamily (2, 6, 7). The similarities among the various subunits of the GlyR, GABAAR, and the nAChR include amino acid sequence identity of between 20 and 35% and predicted topological features, such as a large amino-terminal extracellular domain containing a highly conserved disulfidebonded loop motif and four a-helical transmembrane domains, the latter forming the integral ion channel of this receptor superfamily.Inhibitory glycinergic neurotransmission is antagonized by the convulsive alkaloid strychnine (8). Young and Snyder (9,10) showed that [3H]strychnine could bind with high affinity (Kd = 2-12 nM) (9, 11) to membranes from rat spinal cord. This binding was displaced by glycine, 13-alanine, taurine, and f3-aminoisobutyric acid. Although the binding sites for glycine and strychnine are mutually interactive or overlapping,

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The hyperpolarization of spinal motoneurones by glycine and related amino acids

Cited by 463 publications

References 37 publications

A novel antagonist, phenylbenzene ω‐phosphono‐α‐amino acid, for strychnine‐sensitive glycine receptors in the rat spinal cord

A novel antagonist, phenylbenzene ω‐phosphono‐α‐amino acid, for strychnine‐sensitive glycine receptors in the rat spinal cord

On the pharmacology of the γ‐aminobutyric acid receptors on the cuneo‐thalamic relay cells of the cat

Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.

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