Distribution of GABA A and GABA B receptors in mammalian brain: Potential targets for drug development

GABA is the major inhibitory neurotransmitter in mammalian brain. GABA receptors and the metabolism of GABA are significant targets for new centrally acting drugs to treat neurological and behavioral disorders. The simple neutral amino acid is likely to subserve a neurotransmitter role at 25–50% of all synapses in the central nervous system. GABA's actions are mediated by two different receptors, GABA A and GABA B receptors. GABA A receptors are ligand-gated chloride channels that are sensitive to the convulsant alkaloid bicuculline and modulated by benzodiazepines and barbiturates. GABA B receptors affect calcium and potassium conductance through GTP binding proteins and are insensitive to bicuculline and sensitive to the agonist baclofen. Both receptors are widely distributed in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellum, and brainstem.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50215/1/430210303_ftp.pd

Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice.

Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK

Myoclonus in adult Huntington's disease

Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after the first signs of the disease. Their electroencephalograms were consistent with a primary generalized epilipsy, although neither man had seizures. The myoclonus was controlled with valproic acid therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50341/1/410290217_ftp.pd

Pharmacology of GABA-mediated inhibition of spinal cord neurons in vivo and in primary dissociated cell culture

In this paper it is shown that the postsynaptic GABA-receptor chloride ion channel complex is composed of several functional subunits. There are probably at least two stereospecific locations on the receptor for GABA-binding and both must be occupied to obtain an increase in chloride conductance. The interaction between these sites is uncertain but there could be either positive cooperativity between the sites or only a requirement that both sites are occupied without occupation of either site affecting the affinity for GABA of the other site. There is a chloride conductance channel coupled to the GABA receptor which opens for an average of 20 msec and has an average conductance of 18 pS. The GABA-coupled chloride channel may or may not have the same composition as the glycine coupled chloride channel.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45345/1/11010_2004_Article_BF00235693.pd

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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28692/1/0000512.pd

Tetrahydro-9-aminoacridine (THA) interacts with the phencyclidine (PCP) receptor site

The effect of tetrahydro-9-aminoacridine (THA) and related compounds on ligand binding to the dissociative anesthetic (phencyclidine, PCP) receptor site was assessed using a rat brain homogenate assay. THA displaced the dissociative anesthetic ligand [3H]N-(1-[2-thienyl]cyclohexyl)3-4-piperidine ([3H]TCP) binding with an IC50 of 26 [mu]M. Other acridine derivatives displayed similar potency as displacers of [3H]TCP. Cholinesterase inhibitors and aminopyridines had IC50s equal to or greater than 100 [mu]M. Saturation studies of [3H]TCP in the presence and absence of 30 [mu]M THA revealed competitive inhibition with a K1 of 15 [mu]M. The clinical pharmacology of THA suggests that it antagonizes the effects of dissociative anesthetics whereas in vitro, it behaves as a weak PCP agonist. THA may exert some of its clinical effects through interaction with the PCP receptor, and may have mixed agonist-antagonist properties.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27266/1/0000276.pd