Amino acid transmitters in the mammalian central nervous system

More documents

Recommendations

Info

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
Amino Acid Transmitters in the Mammalian Central Nervous System 119 of sufficient potassium or chloride ions to convert the hyperpolarizing action of glycine into depolarization, failed to modify the depolarization of feline spinal motoneurones induced synaptically or by microelectrophoretic DL-homocysteate or L-glutamate (CURTIS, DUGGAN, FELIX, JOHNSTON, TEBECIS, and WATKINS, 1972 a; ZIE6L6XNSBERGER and PUIL, 1972). These experiments indicate that depolarization may involve a simultaneous increase in membrane permeability to sodium and potassium ions which is unaffected by tetrodotoxin. L-Glutamate and related excitant amino acids promote an influx of sodium ions into brain slices in vitro which is inhibited by tetrodotoxin -- such ion movements are thus distinct from the initial depolarizing action of the amino acids, and probably are those linked with action potentials arising from the depolarization (HARVEY and MCILWAIN, 1969; CURTIS, 1970; BALCAR and JOHNSTON, 1972a). NH 2 NH 2 C2HsOCOCH2CH2CHCOOC2H5 HOOCCH2CH2CCOOH CH 3 L-GLUTAMATE DL-~-METHYL DIETHYL ESTER GLUTAMIC ACID LSD o NH2 CH~ISI Ii CH~CH~CH COON NH L-METHIONINE- DL-SULPHOXlMINE ~ ~ CH3 NH~N2 ~ ;....O \o. OCH3 1-HYDROXY-3-AM INO 2-METHOXYAPORPHINE PYRROLIDONE-2 Fig. 4. Substances reported to antagonize the postsynaptic action of L-glutamate L-Glutamate Antagon&ts. The following compounds have been re.ported as L-glutamate antagonists under certain conditions with varying degrees of selectivity in the feline CNS: LSD (BoAKES, BRADLEY, BRIGGS, and DRAY, 1970), L- glutamate diethyl ester, DL-~-methyl glutamic acid (HALDEMAN, HUFFMAN, MAR- SHALL, and MCLENNAN, 1972), 2-methoxyaporphine, L-methionine-DL- sulphoximine (CURTIS et al., 1972 a) and 1-hydroxy-3-amino- pyrrolidone-2 (DAVXES and WATKINS, 1972). The structures of these compounds (Fig. 4) may provide clues to more useful antagonists. 3.7. Structurally Related Excitant Amino Acids At least two excitant amino acids, in addition to L-glutamate and L-aspartate, occur in normal CNS tissue, albeit in relative low concentrations: L-cysteate and L-cysteine sulphinate. It is possible that others also are present as there are unidentified peaks in amino acid analyses of rat and mouse brain in the regions where the known acidic amino acids are eluted (SHAw and HE1NE, 1965 ; SHIMADA
Page 1 and 2: Amino Acid Transmitters in the Mamm
Page 21: Amino Acid Transmitters in the Mamm
Page 73 and 74:
Amino Acid Transmitters in the Mamm
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
show all

Amino acid transmitters in the mammalian central nervous system

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?