The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Here we have determined three different crystal structures of the extracellular ligand-binding region of mGluR1--in a complex with glutamate and in two unliganded forms. They all showed disulphide-linked homodimers, whose 'active' and 'resting' conformations are modulated through the dimeric interface by a packed alpha-helical structure. The bi-lobed protomer architectures flexibly change their domain arrangements to form an 'open' or 'closed' conformation. The structures imply that glutamate binding stabilizes both the 'active' dimer and the 'closed' protomer in dynamic equilibrium. Movements of the four domains in the dimer are likely to affect the separation of the transmembrane and intracellular regions, and thereby activate the receptor. This scheme in the initial receptor activation could be applied generally to G-protein-coupled neurotransmitter receptors that possess extracellular ligand-binding sites.

SummaryPreviously we produced the whole extracellular region of metabotropic glutamate receptor subtype 1 (mGluR1) in a soluble form. The soluble receptor retained a ligand affinity comparable with that of the full-length membrane-bound receptor and formed a disulfidelinked dimer. Here, we have identified a cysteine residue responsible for the intermolecular disulfide bond and determined domain organization of the extracellular region of mGluR1. A mutant, C140A, was a monomer under nonreduced conditions by SDS-polyacrylamide gel electrophoresis, however, C140A was eluted at the position similar to that of mGluR113, the by guest on

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Objective To compare the effects of diuresis induced by a loop diuretic (frusemide), an osmotic diuretic (mannitol) and a high-osmolar radio-contrast medium (sodium iothalamate) on the intrarenal resistive index (RI) in dogs with chronic unilateral partial ureteric obstruction (UPUO). Materials and methods The split renal clearance and intrarenal RI were estimated in 11 dogs with chronic UPUO. Doppler ultrasonography measurements of the interlobar arteries were obtained before and 10 min after the intravenous infusion of 1 mg/kg frusemide, 1 g/kg mannitol or 20 mL 60% sodium iothalamate. The same experimental protocol was repeated with another drug at 1-week intervals. Results There was a significant difference between the intrarenal RI of obstructed and unobstructed kidneys in the chronic phase of UPUO. While mannitol and sodium iothalamate significantly increased the RI in both kidneys, differences in RI between the kidneys decreased after infusing the two drugs. However, while frusemide insignificantly increased the RI in the obstructed kidney, it decreased the RI in unobstructed one. Consequently, the difference in RI between the kidneys increased significantly after administering frusemide. There were no significant differences in urinary volume after administering each of the drugs. Conclusions As there were no significant differences in the diuretic effects of the drugs, frusemide may have additional effects on the RI of unobstructed kidneys other than diuresis. Frusemide increased the difference between the intrarenal RI of the kidneys and therefore may improve the detection of unilateral urinary obstruction in humans.

The azoospermia factor (AZF) region is important for spermatogenesis, and deletions within these regions are a common cause of oligozoospermia and azoospermia. Although several studies have reported this cause, the present research, to the best of our knowledge, is the first large-scale study assessing this factor in Japan. In this study, 1030 male patients with infertility who were examined for Y chromosome microdeletion using the polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method, a newly developed method for Y chromosome microdeletion screening, were included. The study enrolled 250 patients with severe oligospermia and 717 patients with azoospermia. Among the 1030 patients, 4, 4, 10, and 52 had AZFa, AZFb, AZFb+c, and AZFc deletions, respectively. The sperm recovery rate (SRR) of microdissection testicular sperm extraction in patients with AZFc deletions was significantly higher than that in those without AZF deletions (60.0% vs 28.7%, P = 0.04). In patients with gr/gr deletion, SRR was 18.7%, which was lower than that in those without gr/gr deletion, but was not statistically significant. In conclusion, our study showed that the frequency of Y chromosome microdeletion in male patients in Japan was similar to that reported in patients from other countries, and SRR was higher in patients with AZFc deletion.