Inhibitory glutamate

Inhibitory glutamate receptors (iGlu-Rs) are inhibitory, Glu-gated ion channels related to the ionotropic GABA receptors and glycine receptors, the open channel being permeable to Cl- and sometimes to K+. The isoxazole alkaloid ibotenic acid activates iGlu-Rs (Table 3.3). 

IGF-l-RTK, insulin-like growth factor-1 receptor tyrosine kinase IGF-2, insulin-like growth factor-2 IGF-2-RTK, insulin-like growth factor-2 receptor tyrosine kinase iGlu-R, inhibitory glutamate receptor IKK, inhibitor kB kinase IL, interleukin IL-1P, interleukin-1P IL-ip-R, interleukin-ip receptor IL-1, interleukin-1 IL-8, interleukin-8 IL-8-R, interleukin-8-receptor lie, isoleucine Im, imidazole... 

Etter A, Cully DF, Liu KK, Reiss B, Vassilatis DK, Schaeffer JM, Arena JP (1999) Picrotoxin Blockade of Invertebrate Glutamate Gated Chloride Channels Subunit Dependence and Evidence for Binding within the Pore. J Neurochem 72 318 Cleland TA (1996) Inhibitory Glutamate Receptor Channels. Mol Neurobiol 13 97 Yarowsky J, Carpenter DO (1978) A Comparison of Similar Ionic Responses to y-Amino-butyric Acid and Acetylcholine. J Neurophysiol 41 531... 

Baba A. Saga H, Hashimoto H (1993) Inhibitory glutamate response on cyclic AMP formation in cultured astrocytes. Neurosci Lett /49 182-184. 

Altered synaptic properties Numerous changes in the properties of inhibitory (GABAergic) and excitatory (glutamatergic) synapses have been reported. While the simple adage of an imbalance between inhibitory and excitatory neurotransmission in epilepsy is not generally applicable, some forms of inhibition are lost or impaired in epilepsy. Likewise, an increased function of glutamate receptors has been demonstrated in some brain areas. 

Synaptic vesicles isolated from brain exhibit four distinct vesicular neurotransmitter transport activities one for monoamines, a second for acetylcholine, a third for the inhibitory neurotransmitters GABA and glycine, and a fourth for glutamate [1], Unlike Na+-dependent plasma membrane transporters, the vesicular activities couple to a proton electrochemical gradient (A. lh+) across the vesicle membrane generated by the vacuolar H+-ATPase ( vacuolar type proton translocating ATPase). Although all of the vesicular transport systems rely on ApH+, the relative dependence on the chemical and electrical components varies (Fig. 1). The... 

Lonart G, Johnson KM Inhibitory effects of nitric oxide on the uptake of [3H]dopamine and [3H]glutamate by striatal synaptosomes. J Neurochem 63 2108—2117, 1994 Lovinger DM, White G Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol 40 263—270, 1991... 

Unlike other transmitter systems, there are no obvious meehanisms for dampening glutamate release. Presynaptic autoreceptors for glutamate are mostly of the kainate type (see below) and appear to act as positive rather than negative influenees on further release of the amino acid. Although poorly characterised at present, inhibitory autoreceptors of the metabotropic type of receptors may act to inhibit release of glutamate. 

Normally (Fig. 15.2(a)) DA inhibits the Ind Path to GPext so that this is then free to inhibit the SThN. This latter system can then no longer drive, through glutamate release, the SNr or GPint whose inhibitory outputs are reduced. The assumption is that the thalamo-cortical pathway can then function properly and movement is normal. 

Figure 15.9 Peptide modulation of striatal input to the globus pollidus. Enkephalin released from axon terminals of neurons of the indirect pathway (see Fig. 15.2 for details) is thought to inhibit GABA release from the same terminals so that feedback (auto) inhibition is reduced. This will free the neurons to inhibit the subthalamic nucleus (SThN) and its drive to GPint and SNr which in turn will have less inhibitory effect on cortico-thalamic traffic and possibly reduce akinesia. Dynorphin released from terminals of neurons of the direct pathway may also reduce glutamate release and excitation in the internal globus pallidus and further depress its inhibition of the cortico-thalamic pathway. High concentrations of these peptides may, however, result in dyskinesias. (See Henry and Brotchie 1996 and Maneuf et al. 1995)...

In addition to the loss of GAD staining (i.e. GABA) neurons and inhibitory symmetrical synapses around an alumina focus in primates (see above), studies with a chronically implanted cortical cup over a cobalt lesion (focus) in rats show an increased release of glutamate that is associated with spiking (Dodd and Bradford 1976). 

It was found, however, that if neuroleptic administration was continued for two weeks then neuronal firing stopped. Also while the neurons could not be made to fire by the excitatory NT glutamate, the inhibitory NT GABA activated them by reducing the... 

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

Opiates produce more discreet inhibitory effects since they bind to and activate inhibitory opioid receptors which, due to their restricted distribution, cause less widespread effects than those of the barbiturates and alcohol. Activation of the opioid receptors leads to a decrease in release of other neurotransmitters (glutamate, NA, DA, 5-HT, ACh, many peptides, etc.) and direct hyperpolarisation of cells by opening of K+ channels and decreasing Ca + channel activity via predominant actions on the mu opiate receptor (see Chapter 12). 

Status epilepticus occurs because the brain fails to stop an isolated seizure. The exact reason for this failure is unknown and probably involves many mechanisms. A seizure is likely to occur due to a mismatch of excitatory and inhibitory neurotransmitters in the brain. The primary excitatory neurotransmitter in the brain is glutamate. Glutamate stimulates postsynaptic N-methyl-D-aspartate (NMDA) receptors in the brain, causing an influx of calcium into the cells and depolarization of the neuron. Sustained depolarization may maintain SE and eventually cause neuronal injury and death.7 The primary... 

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