Amino acid transmitters in the mammalian central nervous system

118 D.R. CURTIS and G. A. R. JOHNSTON"
"large" L-glutamate pool), but enters the "small" pool in which it is converted
to L-glutamine by the action of L-glutamine synthetase. The L-glutamate in
the "large" pool appears to be synthesised predominantly from D-glucose and
intermediates of glycolysis, and may represent "transmitter" L-glutamate in addition
to L-glutamate involved in energy metabolism related to electrical and general
metabolic activity. The "small" pool may be associated with glial cells and may
represent "inactivated" L-glutamate taken up from the synaptic cleft after synaptic
release.
L-Glutamate Transport. At least two kinetically distinct transport systems
have been described for L-glutamate in isolated brain tissue. The system of
higher Km, the "low affinity" system, seems to be a general property of many
subcellular particles, whereas the system of lower Km, the "high affinity" system,
is associated with a unique population of subcellular particles (Rat: WOVSEY
et al,, 1971 ; LOGAN and SNYDER, 1972). Neither system is specific for L-glutamate,
but may transport a variety of acidic, amino acids including L-aspartate and
L-cysteate (COHEN and LAJTHA, 1972; Rat: BALCAR and JOHNSTON, 1972a, b).
The "high affinity" system shows an absolute dependence on sodium ions (Rat:
BENNETT et al., 1972). The possible relationship between the high and low affinity
uptake systems and the two pools of L-glutamate metabolism is at present unknown.
L-Glutamate uptake is inhibited by various drugs including juglone, chlorpromazine
and p-chloromercuriphenylsulphonate (Cat, rat: BALCAR and JOHNSTON,
1972 a, b, 1973): the latter when administered microelectrophoretically enhances
the excitant action of L-glutamate on feline spinal interneurones (CURTIS et al.,
1970b).
L-Glutamate Release. The release of endogenous L-glutamate in vivo from
the surface of the feline cerebral cortex is increased by brain stem stimulation
(JASPER and KOYAMA, 1969), and in vitro that from synaptosomes by electrical
field stimulation (Rat: BRADFORD, 1970). The release of exogenous L-glutamate
in vitro from slices of rat brain and spinal cord following electrical field stimulation
or stimulation by increased extracellular potassium ions has also been reported
(MITCHELL et al., 1969; ARNFRED and HERZ, 1971 ; HOPKIN and NEAL, 1971).
Postsynaptie Action of L-Glutamate. L-Glutamate and structurally related
acidic amino acids excite feline central neurones by a reversible depolarization
accompanied by an increase in membrane conductance (CuRTlS et al., 1960;
KRNJEVI~ and SCHWARTZ, 1967a, ZIEGLG~,NSBERGER and PUIL, 1973). D-Homocysteate,
N-methyl-D-aspartate and fl-N-oxalyl-L-c~,fl-diaminopropionate are
more powerful excitants than L-aspartate and L-glutamate, which in turn are
slightly stronger than their corresponding D-isomers (CURTIS and WATKINS, 1963 ;
WATKINS, CURTIS, and BISCOE, 1966). Analysis of the complete ionic mechanism
of amino acid-induced depolarization, or indeed of synaptic excitation, raises
considerable experimental difficulties since the majority of excitatory synapses
upon neurones are located on the dendrites. However comparisons of the "reversal"
potentials for amino acid depolarization and synaptic excitation (CURTIS,
1965; ZIEGLG,g, NSBERGER and PUIL, 1973) indicate that the two types of depolarization
could involve the same change of membrane ion conductance. Furthermore,
the extracellular administration of tetrodotoxin, or the intracellular injection