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Reduced expression of the mu-isozyme of glutathione S-transferase (GST; EC 2.5.1.18) has been associated with increased lung cancer risk. We studied the association between GST-mu expression and DNA damage as measured by sister chromatid exchanges (SCE) in healthy male smokers. SCE levels were higher in the 71 GST-mu-deficient smokers compared to the 83 non-deficient smokers (5.24 versus 4.97 SCE/lymphocyte; P = 0.09). In smokers having high plasma cotinine levels (greater than median of 315 ng/ml), this mu-related difference was more pronounced (5.50 versus 4.97; P = 0.01), whereas it was absent in smokers having low cotinine levels (4.95 versus 4.97; P = 0.92). Increased cytogenetic damage in GST-mu-deficient heavy smokers may thus explain the association between GST-mu expression and lung cancer.

The strychnine-sensitive glycine receptor (GlyR) is a ligandgated ion channel that mediates fast synaptic inhibition in the vertebrate central nervous system. As a member of the family of Cys-loop receptors, it assembles from five homologous subunits (GlyR␣1-4 and -␤). Each subunit contains an extracellular ligand binding domain, four transmembrane domains (TM), and an intracellular domain, formed by the loop connecting TM3 and TM4 (TM3-4 loop). The TM3-4 loops of the subunits GlyR␣1 and -␣3 harbor a conserved basic motif, which is part of a potential nuclear localization signal. When tested for functionality by live cell imaging of green fluorescent protein and ␤-galactosidase-tagged domain constructs, the TM3-4 loops of GlyR␣1 and -␣3, but not of GlyR␣2 and -␤, exhibited nuclear sorting activity. Subunit specificity may be attributed to slight amino acid alterations in the basic motif. In yeast two-hybrid screening and GST pulldown assays, karyopherin ␣3 and ␣4 were found to interact with the TM3-4 loop, providing a molecular mechanism for the observed intracellular trafficking. These results indicate that the multifunctional basic motif of the TM3-4 loop is capable of mediating a karyopherin-dependent intracellular sorting of full-length GlyRs.In the vertebrate nervous system, signal transmission at chemical synapses is mediated by ionotropic and metabotropic neurotransmitter receptors. Ligand-gated ion channels harbor an intrinsic channel pore that is opened almost instantly upon ligand binding. Among the ligand-gated ion channels, the superfamily of Cys-loop receptors comprises the nicotinic acetylcholine receptor, the 5-hydroxytryptamine type 3 receptor, the ␥-aminobutyric acid type A/C receptor, and the GlyR. Besides sequence homology, Cys-loop receptors share a common pentameric rosette-like composition of homologous subunits and a characteristic subunit topology (Fig.

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