Excitatory amino acid transmitters

Glutamate is ubiquitously distributed in brain tissue, where it is present in a higher concentration than any other amino acid. During the last 50 years glutamate in brain has been the subject of numerous studies, and several different functions have been ascribed to it. Early studies by Krebs (1935) suggested that glutamate played a central metabolic role in brain. The complex compartmentation of glutamate metabolism in brain was first noted by Waelsch and coworkers (Berl et al., 1961). These studies were precipitated by the claim that glutamate improved mental behaviour and was beneficial in several neurological disorders including epilepsy and mental retardation. Other scientists pointed out its function in the detoxification of ammonia in brain (Weil-Malherbe, 1950). Glutamate is also an important building block in the synthesis of proteins and peptides, including glutathione (Meister, 1979). The toxic effect of administered glutamate and its analogues kainic acid, ibotenic acid, and N-methyl aspartic acid on CNS neurones has become a large and independent line of research (Lucas and Newhouse, 1957; Olney et al., 1974; Lund-Karlsen and Fonnum, 1976; Coyle, 1983). Attention has also been focused on the role of glutamate as a precursor for the inhibitory neurotransmitter y-aminobutyric acid (GABA) (Roberts and Frankel, 1950). Electrophysiological studies (Curtis and Watkins, 1961) focused early on the powerful and excitatory action of glutamate on spinal cord neurones. Since the action was widespread and effected by both the Dand Lforms, it was at first difficult to believe that glutamate could be a neurotransmitter. During the last 15 years, however, several studies have provided support for the concept that glutamate is a transmitter in brain (for review see Curtis and Johnston, 1974; Fonnum, 1978; 1981; Roberts et al., 1981; DiChiara and Gessa, 1981). Glutamate satisfies today to a large extent the four main criteria for classification as a neurotransmitter: (1) it is presynaptically localized in specific neurones; (2) it is specifically released by physiological stimuli in concentrations high enough to elicit postsynaptic response; (3) it demonstrates identity of action with the naturally occurring transmitter, including response to antagonists; and (4) mechanisms exist that will terminate transmitter action rapidly. The evidence for glutamate as a transmitter at the locust neuromuscular junction has recently been carefully evaluated by Usherwood (1981). In that case the identity of action of glutamate with the naturally occurring transmitter on the neuromuscular receptor, the release from nerve terminals, and its similarity to acetylcholine at the mammalian neuromuscular junction with regard to presynaptic pharmacology and denervation supersensitivity are compelling evidence for glutamate as a neurotransmitter. The main methods used to identify glutamergic pathways in brain will be critically reviewed and discussed. The effect of lesions on high-affinity uptake and release are particularly important, but immunohistochemical methods to study enzymes and glutamate itself are becoming more interesting. The release of glutamate has been demonstrated by several different procedures using both in vivo and in vitro preparations. The synthesis of large groups of specific agonists and antagonists has been important both for identification and characterization of the glutamate receptor by electrophysiological techniques and for the isolation of glutamate receptors. High and perhaps low-affinity uptake into nerve terminals and glial cells is important for the termination of transmitter action. Particular attention is given in this review to the complex compartmentation of glutamate synthesis and the possibility of identifying the transmitter pool of glutamate.

Glutamate: a neurotransmitter in mammalian brain.

The first edition of this highly acclaimed reference work was published in 1980. Since then no other book has approached the breadth, scholarship and the balance of this book. For this long-awaited second edition, the original editors have been joined by Albert Ludolph, who brings in expertise in biological neurotoxicology. In the introductory chapters, an overview of the biological basis of neurotoxicity provides the groundwork for discussing the scope of human and veterinary neurotoxic disease. The bulk of the text is devoted to an encyclopaedic treatment of chemicals with neurotoxic potential. This consists of tightly written overviews of the properties, actions and mechanisms of all manner of substances, whether natural or synthetic. The neurotoxic mechanisms of experimental agents and adverse effects of therapeutic and abused drugs are covered extensively. Environmental pollutants, workplace contaminants, personal-use products, food additives and agents harboured by plants, animals and humans for use against their respective enemies are all included. Each substance is rated on a three-point scale for the weight of evidence indicating a specific neurotoxic effect in humans, animals, or laboratory models. These effects are summarised and cross-referenced in a series of appendices and an extensive index. This book will be indispensable to experimental neuroscientists, toxicologists, and practitioners of human and animal medicine. It also provides an authoritative, critical and pithy reference work for public health specialists and those within the legal profession.

Experimental and clinical neurotoxicology

Damp indoor spaces and health , Damp indoor spaces and health , کتابخانه دیجیتال جندی شاپور اهواز

Damp Indoor Spaces and Health

Tremorgenic indole alkaloids produce neurological disorders (e.g., staggers syndromes) in ruminants. The mode of action of these fungal mycotoxins is not understood but may be related to their known effects on neurotransmitter release. To determine whether these effects could be due to inhibition of K+ channels, the interaction of various indole diterpenes with high-conductance Ca(2+)-activated K+ (maxi-K) channels was examined. Paspalitrem A, paspalitrem C, aflatrem, penitrem A, and paspalinine inhibit binding of [125I]charybdotoxin (ChTX) to maxi-K channels in bovine aortic smooth muscle sarcolemmal membranes. In contrast, three structurally related compounds, paxilline, verruculogen, and paspalicine, enhanced toxin binding. As predicted from the binding studies, covalent incorporation of [125I]ChTX into the 31-kDa subunit of the maxi-K channel was blocked by compounds that inhibit [125I]ChTX binding and enhanced by compounds that stimulate [125I]ChTX binding. Modulation of [125I]ChTX binding was due to allosteric mechanisms. Despite their different effects on binding of [125I]ChTX to maxi-K channels, all compounds potently inhibited maxi-K channels in electrophysiological experiments. Other types of voltage-dependent or Ca(2+)-activated K+ channels examined were not affected. Chemical modifications of paxilline indicate a defined structure-activity relationship for channel inhibition. Paspalicine, a deshydroxy analog of paspalinine lacking tremorgenic activity, also potently blocked maxi-K channels. Taken together, these data suggest that indole diterpenes are the most potent nonpeptidyl inhibitors of maxi-K channels identified to date. Some of their pharmacological properties could be explained by inhibition of maxi-K channels, although tremorgenicity may be unrelated to channel block.

Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels.

The neurochemical effects of the tremorgenic mycotoxins Verruculogen and Penitrem A, which produce a neurotoxic syndrome characterised by sustained tremors, were studied using sheep and rat synaptosomes. The toxins were administered in vivo, either by chronic feeding (sheep) or intraperitoneal injection 45 min prior to killing (rat), and synaptosomes were subsequently prepared from cerebrocortical and spinal cord/medullary regions of rat, and corpus striatum of sheep. Penitrem A (400 mg mycelium/kg) increased the spontaneous release of endogenous glutamate, GABA (gamma-aminobutyric acid), and aspartate by 213%, 455%, and 277%, respectively, from cerebrocortical synaptosomes. Verruculogen (400 mg mycelium/kg) increased the spontaneous release of glutamate and aspartate by 1300% and 1200%, respectively, but not that of GABA from cerebrocortical synaptosomes. The spontaneous release of the transmitter amino acids or other amino acids was not increased by the tremorgens in spinal cord/medullary synaptosomes. Penitrem A pretreatment reduced the veratrine (75 microM) stimulated release of glutamate, aspartate, and GABA from cerebrocortical synaptosomes by 33%, 46%, and 11%, respectively, and the stimulated release of glycine and GABA from spinal cord/medulla synaptosomes by 67% and 32% respectively. Verruculogen pretreatment did not alter the veratrine-induced release of transmitter amino acids from cerebrocortex and spinal cord/medulla synaptosomes. Penitrem A pretreatment increased the spontaneous release of aspartate, glutamate, and GABA by 68%, 62%, and 100%, respectively, from sheep corpus striatum synaptosomes but did not alter the synthesis and release of dopamine in this tissue. Verruculogen was shown to cause a substantial increase (300-400%) in the miniature-end-plate potential (m.e.p.p.) frequency at the locust neuromuscular junction. The response was detectable within 1 min, rose to a maximum within 5-7 min, and declined to the control rate over a similar period. No change in the amplitude of the m.e.p.p.'s was observed. These effects of the tremorgens on transmitter release are interpreted in terms of their mode of action.

R. H. C. Penny

Papers

Actions of Tremorgenic Fungal Toxins on Neurotransmitter Release