Could ethanol-induced alterations in the expression of glutamate transporters in testes contribute to the effect of paternal drinking on the risk of abnormalities in the offspring?

It has been known that a preconception paternal alcoholism impacts adversely on the offspring but the mechanism of the effect is uncertain. Several findings suggest that there are signalling systems in testis that are analogous to those known to be altered by alcoholism in brain. We propose that chronic alcohol affects these systems in a manner similar to that in brain. Specifically, we hypothesise that excessive alcohol may disturb glutamatergic-like signalling in testis by increasing expression of the glutamate transporter GLAST (EAAT1). We discuss ways how to test the hypothesis as well as potential significance of some of the tests as tools in the diagnostics of chronic alcoholism

Cardiac Glycosides Ouabain and Digoxin Interfere with the Regulation of Glutamate Transporter GLAST in Astrocytes Cultured from Neonatal Rat Brain

Glutamate transport (GluT) in brain is mediated chiefly by two transporters GLT and GLAST, both driven by ionic gradients generated by (Na+, K+)-dependent ATPase (Na+/K+-ATPase). GLAST is located in astrocytes and its function is regulated by translocations from cytoplasm to plasma membrane in the presence of GluT substrates. The phenomenon is blocked by a naturally occurring toxin rottlerin. We have recently suggested that rottlerin acts by inhibiting Na+/K+-ATPase. We now report that Na+/K+-ATPase inhibitors digoxin and ouabain also blocked the redistribution of GLAST in cultured astrocytes, however, neither of the compounds caused detectable inhibition of ATPase activity in cell-free astrocyte homogenates (rottlerin inhibited app. 80% of Pi production from ATP in the astrocyte homogenates, IC50 = 25 μM). Therefore, while we may not have established a direct link between GLAST regulation and Na+/K+-ATPase activity we have shown that both ouabain and digoxin can interfere with GluT transport and therefore should be considered potentially neurotoxic

Activity-dependent γ-aminobutyric acid release controls brain cortical tissue slice metabolism

Vigabatrin (γ-vinyl-GABA) is an irreversible inhibitor of the enzyme γ-aminobutyric acid (GABA) transaminase. It has been shown to increase levels of GABA in brain and result in increased release of GABA from nonsynaptic sources following activation. Here, we use a guinea pig cortical tissue slice model to identify the metabolic sequelae of vigabatrin when incubated with tissue slices alone or when the tissue slices were activated by ligands with targeted activating mechanisms. We show that incubation of slices with AMPA, the group II metabotropic glutamate antagonist EGLU [(2S)-α-ethylglutamic acid], or the GABA BR antagonist CGP 52432 in the presence of vigabatrin produces very similar metabolic profiles, consistent with the large-scale turning off of metabolic activity. This effect is blocked by the GABA Arho antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. Taken together, these results suggest that GABA, released following activation, acts on extrasynaptic receptors consistent with GABA Arho and that these receptors act as a kind of "master switch" that is capable of turning off a range of differently induced activities

Human brain neurons express a novel splice variant of excitatory amino acid transporter 5 (hEAAT5v)

Excitatory amino acid transporter 5 (EAAT5) is a protein that is known to be alternately spliced and to be abundantly expressed in the retina by populations of neurons including photoreceptors and bipolar cells. EAAT5 acts as a slow glutamate transporter and also as glutamate-gated chloride channel, the chloride conductance being large enough for EAAT5 to serve functionally as an “inhibitory” glutamate receptor. However, there has been a long-standing view that the classically spliced form of EAAT5 is not abundant or widespread in the brain and so it has not been extensively investigated in the literature. We recently identified a human-specific splicing form of EAAT5 that was not expressed by rodents but was shown to be a functional glutamate transporter. We have examined the expression of this form of EAAT5, hEAAT5v at the mRNA, and protein level in human brain, and show that populations of human cortical pyramidal neurons and cerebellar Purkinje cells show significant expression of hEAAT5v. Accordingly, we infer that EAAT5 may well be a player in modulating neuronal function in the human brain and propose that its localization in both glutamatergic and GABAergic neurons could be compatible with a role in influencing intracellular chloride and thereby neuronal parameters such as membrane potential rather than acting as a presynaptic glutamate transporter

CD36 gene polymorphism is associated with Alzheimer's disease.

IF 3.112International audienceCD36 gene encodes a membrane glycoprotein (type B scavenger receptor) present on the surface of many types of cells and having multiple cellular functions ranging from angiogenesis to gustatory perception of fatty acids. Using a case control genetic association approach we have analyzed selected single nucleotide polymorphisms (SNP's) in a total of 859 patients with Alzheimer's disease (AD) and controls and have identified the allele A in rs3211892 polymorphism of CD36 gene as significantly increasing the risk of AD. Additionally we have investigated, in the same sample of control subjects and patients, SNP's in ApoE gene and confirmed that the previously identified AD-associated SNP's indeed increased the risk and decreased the age of onset of AD as reported by others earlier. Based on the current knowledge of CD36 biochemistry we propose that the AD risk-imparting variants of CD36 alter cholesterol homeostasis, oxidation stress or induce pathological inflammatory cascades. The SNP rs3211892 has previously been associated with heart disease and other conditions but the present study is the first to identify a significant association between variations in CD36 gene and the risk of Alzheimer's disease

Metabolomic approaches to defining the role(s) of GABAρ receptors in the brain

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABA(rho) receptors, defined by their characteristic pharmacology and presence of rho subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors. We compared metabolic fingerprints generated by a range of ligands active at GABA(rho) and included these in a principal components analysis with a library of other metabolic fingerprints obtained using ligands active at GABA(A) and GABA(B), with inhibitors of GABA uptake and with compounds acting to inhibit enzymes active in the GABAergic system. This enabled us to generate a metabolic "footprint" of the GABAergic system which revealed classes of metabolic activity associated with GABA(rho) which are distinct from other GABA receptors. Antagonised GABA(rho) produce large metabolic effects at extrasynaptic sites suggesting they may be involved in tonic inhibition