The neurotransmitter candidature of sulphur-containing excitatory amino acids in the mammalian central nervous system

doi:10.1016/S0163-7258(96)00097-6

Pharmacology & Therapeutics

Volume 72, Issue 1, 1996, Pages 25-36

https://doi.org/10.1016/S0163-7258(96)00097-6 Get rights and content

Abstract

While l-glutamate (l-Glu) is considered to be the predominant excitatory amino acid transmitter in the mammalian CNS, other amino acids have come under scrutiny as possible rivals for such a role. These include four sulphur-containing analogues of l-Glu and l-aspartate known as the SAAs. The l-Glu analogues are l-homocysteic acid and l-homocysteine sulphinic acid, while the l-aspartate analogues are l-cysteic acid and l-cysteine sulphinic acid. They are mixed agonists of excitatory amino acid receptors on a variety of neurones and are reported to be present in and released from mammalian CNS tissue. This review serves to summarize the current state of research into the possibility that one or more of these compounds is indeed a transmitter within the mammalian CNS.

References (109)

K.J. Anderson et al.
Anatomical and pharmacological heterogeneity of d-[³H]aspartate binding sites
Eur. J. Pharmacol.
(1990)
A. Baba
Neurochemical characterization of cysteine sulfinic acid, an excitatory ammo acid, in hippocampus
Jpn. J. Pharmacol.
(1987)
V.J. Balcar et al.
Na⁺-dependent high affinity uptake of l-glutamate in primary cultures of human fibroblasts isolated from three different types of tissue
FEBS Lett.
(1994)
R.J. Baldessarini
Neuropharmacology of S-adenosyl-L-methionine
Am. J. Med.
(1987)
S. Bernath
Calcium-independent release of amino acid neurotransmitters: fact or artifact?
Prog. Neurobiol.
(1992)
B. Bettler et al.
Review: neurotransmitter receptors II, AMPA and kainate receptors
Neuropharmacology
(1995)
D.J. Chalmers et al.
Differential actions of 3-(4-chlorophenyl)-glutamic acid stereoisomers and l-trans-pyrrolidine-2,4-dicarboxylic acid upon l-homocysteic acid- and l-glutamic acid-induced responses from rat spinal motoneurones
Neuropharmacology
(1995)
M.J. Christie et al.
Excitotoxic lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area
Brain Res.
(1985)
N.C Danbolt
The high affinity uptake system for excitatory amino acids in the brain
Prog. Neurobiol.
(1994)
J. Davies et al.
Selective potentiating effect of β-p-chlorophenylglutamate on responses induced by certain sulphur-containing excitatory amino acids and quisqualate
Neuropharmacology
(1985)

J. De la Rosa et al.

Evidence for a rate limiting role of cysteinesulfinate decarboxylase activity in taurine biosynthesis in vivo

Comp. Biochem. Physiol.

(1985)

R. Dingledine et al.

Excitatory amino acid receptors in epilepsy

Trends Pharmacol. Sci.

(1990)

C. Di Padova

S-adenosylmethionine in the treatment of osteoarthritis: review of the clinical studies

Am. J. Med.

(1987)

J. Dunlop et al.

Characterization of the receptormediated sulphur amino acid-evoked release of [³H]-d-aspartate from primary cultures of cerebellar granule cells

Neurochem. Int.

(1990)

J. Dunlop et al.

Sulphur-containing excitatory amino acid-evoked Ca²⁺-independent release of d-[³H]aspartate from cultured cerebellar granule cells: the role of glutamate receptor activation coupled to reversal of the acidic amino acid plasma membrane carrier

Neuroscience

(1992)

P.T. Francis et al.

Brain amino acid concentrations and Ca²⁺-dependent release in intractable depression assessed antemortem

Brain Res.

(1989)

D. Goroll et al.

Ontogenic changes in the hypothalamic levels of amino acid neurotransmitters in the female rat

Dev. Brain Res.

(1994)

A. Grieve et al.

Simultaneous measurement by HPLC of the excitatory amino acid transmitter candidates homocysteate and homocysteine sulphinate supports a predominant astrocytic localisation

Neurosci. Lett.

(1992)

A. Grieve et al.

Kinetic characterization of sulphur-containing excitatory amino acid uptake in primary cultures of neurons and astrocytes

Neurochem. Int.

(1991)

O.W. Griffith

Cysteine sulphinate metabolism: altered partitioning between transamination and decarboxylation following administration of β-methylene aspartate

J. Biol. Chem.

(1983)

O.W. Griffith

Mammalian sulfur amino acid metabolism: an overview

Methods Enzymol.

(1987)

R. Griffiths et al.

Neuronal and glial plasma membrane carrier-mediated uptake of l-homocysteate is not selectively blocked by β-p-chlorophenylglutamate

Neurosci. Lett.

(1992)

M.T.E. Heafield et al.

Plasma cysteine and sulphate levels in patients with Motorneurone, Parkinson's and Alzheimer's disease

Neurosci. Lett.

(1990)

P.L. Herrling et al.

Differential effects of (d)-and (l)-homocysteic acid on the membrane potential of cat caudate neurons in situ

Neuroscience

(1989)

S. Ito et al.

l-Homocysteic acid mediates synaptic excitation at NMDA receptors in the hippocampus

Neurosci. Lett.

(1991)

Y. Kanai et al.

The elusive transporters with high affinity for glutamate

Trends Neurosci.

(1993)

I.C. Kilpatrick et al.

An initial analysis of the regional distribution of excitatory sulphur-containing amino acids in the rat brain

Neurosci. Lett.

(1986)

I.C. Kilpatrick et al.

Uniform distribution of CSA undermines neurotransmitter role

Trends Pharmacol. Sci.

(1991)

J.M. Klancnik et al.

Release of endogenous amino acids, including homocysteic and cysteine sulphinic acid from rat hippocampal slices evoked by electrical stimulation of Schaffer collateralcommissural fibres

Neuroscience

(1992)

T. Knöpfel et al.

l-Homocysteic acid but not l-glutamate is an endogenous N-methyl-D-aspartic acid receptor preferring agonist in rat neocortical neurons in vitro

Neurosci. Lett.

(1987)

M. Lee et al.

Differential effects of N-methyl-D-aspartate and l-homocysteate on cerebellar Purkinje neurons

Brain Res.

(1988)

W.F. Maragos et al.

Glutamate dysfunction in Alzheimer's disease: An hypothesis

Trends Neurosci.

(1987)

M.L. Mayer et al.

The physiology of excitatory amino acids in the vertebrate central nervous system

Prog. Neurobiol.

(1987)

B. Meldrum et al.

Excitatory amino acid neurotoxicity and neurodegenerative diesease

Trends Pharmacol. Sci.

(1990)

D. Minc-Golomb et al.

Cysteine sulfinic acid-induced release of d-(³H)aspartate and (¹⁴C)GABA in hippocampus slices: the role of sodium channels and cAMP

Brain Res.

(1989)

M.J. Neal et al.

l-Homocysteic acid: a possible bipolar cell transmitter in the rabbit retina

Neurosci. Lett.

(1989)

J.W. Olney et al.

l-Homocysteic acid: an endogenous excitotoxic ligand of the NMDA receptor

Brain Res. Bull.

(1987)

F. Ortega et al.

Homocysteate-like immunoreactivity in multiform glioblastoma of human brain

Neurosci. Lett.

(1994)

B. Parsons et al.

Localisation of cysteine sulfinic acid uptake sites in rat brain by quantitative autoradiography

Brain Res.

(1984)

J.W. Phillis

S-adenosylmethionine excites rat cerebral cortical neurons

Brain Res.

(1981)

J-P. Pin et al.

The metabotropic glutamate receptors: structure and functions

Neuropharmacology

(1995)

R.H.P. Porter et al.

Glutamate metabotropic receptor activation in neonatal rat cerebral cortex by sulphur-containing excitatory amino acids

Neurosci. Lett.

(1993)

M. Recasens et al.

Evidence for cysteine sulphinate as a neurotransmitter

Brain Res.

(1982)

M. Recasens et al.

Separate binding sites in rat brain synaptic membranes for l-cysteine sulfinate and l-glutamate

Neurochem. Int.

(1983)

P.W. Robbins et al.

Isolation and identification of active sulfate

J. Biol. Chem.

(1957)

M.B. Robinson et al.

Pharmacologically distinct sodium-dependent l-(³H)glutamate transport processes in rat brain

Brain Res.

(1991)

M. Sandberg et al.

Liquid Chromatographic determination of acidic β-aspartyl and γ-glutamyl peptides in extracts of rat brain

Anal. Biochem.

(1994)

T.W. Stone et al.

Quinolinic acid: a potent endogenous excitant at amino acid receptors in the CNS

Eur. J. Pharmacol.

(1981)

M. Szatkowski et al.

Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms

Trends Neurosci.

(1994)

G.A. Thompson et al.

The actions of a range of excitatory amino acids at (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD)-depolarising receptors on neonatal rat motoneurones

Neuropharmacology

(1995)

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The neurotransmitter candidature of sulphur-containing excitatory amino acids in the mammalian central nervous system

Abstract

Eur. J. Pharmacol.

Jpn. J. Pharmacol.

FEBS Lett.

Am. J. Med.

Prog. Neurobiol.

Neuropharmacology

Neuropharmacology

Brain Res.

Prog. Neurobiol.

Neuropharmacology

Comp. Biochem. Physiol.

Trends Pharmacol. Sci.

Am. J. Med.

Neurochem. Int.

Neuroscience

Brain Res.

Dev. Brain Res.

Neurosci. Lett.

Neurochem. Int.

J. Biol. Chem.

Methods Enzymol.

Neurosci. Lett.

Neurosci. Lett.

Neuroscience

Neurosci. Lett.

Trends Neurosci.

Neurosci. Lett.

Trends Pharmacol. Sci.

Neuroscience

Neurosci. Lett.

Brain Res.

Trends Neurosci.

Prog. Neurobiol.

Trends Pharmacol. Sci.

Brain Res.

Neurosci. Lett.

Brain Res. Bull.

Neurosci. Lett.

Brain Res.

Brain Res.

Neuropharmacology

Neurosci. Lett.

Brain Res.

Neurochem. Int.

J. Biol. Chem.

Brain Res.

Anal. Biochem.

Eur. J. Pharmacol.

Trends Neurosci.

Neuropharmacology