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The g isozyme of diacylglycerol kinase (DGK) is highly expressed in the hippocampus and Purkinje cells in the central nervous system. Recently, several genome-wide association studies have implicated DGKg in the etiology of bipolar disorder (BPD). However, it is still unknown whether DGKg is indeed related to BPD. In this study, we generated DGKg-knockout (KO) mice and performed behavioral tests such as the open field test, the elevated plus maze test and tail suspension test using the KO mice to investigate the effects of DGKg deficits on psychomotor behavior. Intriguingly, DGKg-KO mice displayed an overall behavioral profile that is similar to human mania, including hyperactivity, less anxiety and less depression-like behavior. In addition, these phenotypes were significantly attenuated by the administration of a BPD (mania) remedy, namely, lithium. Moreover, DGKg-KO mice showed impairment in glycogen synthase kinase (GSK) 3b signaling, which is closely related to BPD. These findings clearly support the linkage between BPD and DGKg that is implicated by genome-wide association studies. Moreover, this study provides DGKg-KO mice as a previously unrecognized model that reflects several features of human BPD with manic episodes and revealed an important role for DGKg in regulating behavior and mood through, at least in part, GSK3b signaling.

To investigate the behaviour of red cells in the microcirculation, we established a new capillary method using narrow fluorinated ethylenepropylene copolymer tubes with internal diameters of 12.5 and 25.0 microns. Red cell flow in the tubes under a given range of pressure was analysed through a video system connected to a microscope. The experimental condition was adjusted so that the velocity of the control normocytes would be compatible with that in corresponding vessels in vivo, 0.5-1.5 mm/s. In the 12.5 microns tube, normocytes obtained from 12 young normal volunteers ran in an axisymmetric edge-on orientation with a folded shape at higher pressures, but rolled along freely without deformation at lower pressures. Deformation during the passage of the microcytes obtained from four patients with polycythaemia vera complicated with iron-deficient microcytosis and 10 patients with iron deficiency anaemia was relatively mild, whereas that of the macrocytes obtained from eight patients with refractory anaemia was marked. Even after the screening effect at the tube entrance was taken into consideration, the velocities of both microcytes and macrocytes were found to be significantly lower than the control normocytes. Therefore this method may be a new way to investigate the flow properties of red cells in the microcirculation.

Diacylglycerol kinase (DGK) participates in regulating the intracellular concentrations of two bioactive lipids, diacylglycerol and phosphatidic acid. DGKη1 is a type II isozyme that contains a pleckstrin homology (PH) domain and a pair of C1 domains at the N-terminus and separated catalytic domains (catalytic subdomain-a and b). We previously reported that DGKη1 expressed in COS-7 cells is translocated from the cytoplasm to punctate granules that partially include endosomes in response to stress stimuli such as osmotic shock. However, the biochemical properties of the stress-dependent behaviour of DGKη1 remain unknown. Here, we have found that DGKη1 is redistributed from the cytosol to the non-ionic detergent (Nonidet P-40)-resistant membrane (DRM) in response to osmotic shock. Our results strongly suggested that the Nonidet P-40 insolubility of DGKη1 is due to neither cytoskeleton localization nor lipid raft association, implying that DGKη1 is distributed to detergent-resistant membrane microdomains that have a low lipid-to-protein ratio. We revealed, using a series of DGKη1 deletion mutants, that the PH and C1 domains play a pivotal role in osmotic shock-dependent DRM redistribution, whereas catalytic subdomain-a negatively regulates the event.

BackgroundWe have revealed that the type II diacylglycerol kinases (DGKs) δ, η and κ were expressed in the testis and ovary. However, these enzymes’ functions in the reproductive organs remain unknown.ResultsIn this study, we first identified the expression sites of type II DGKs in the mouse reproductive organs in detail. Reverse transcription-polymerase chain reaction and Western blotting confirmed that DGKδ2 (splicing variant 2) but not DGKδ1 (splicing variant 1) and DGKκ were expressed in the testis, ovary and uterus. DGKη1 (splicing variant 1) but not DGKη2 (splicing variant 2) was strongly detected in the ovary and uterus. Interestingly, we found that a new alternative splicing product of the DGKη gene, DGKη3, which lacks exon 26 encoding 31 amino acid residues, was expressed only in the testis. Moreover, we investigated the distribution of type II DGKs in the testis, ovary and uterus through in situ hybridization. DGKδ2 was distributed in the primary spermatocytes of the testis and ovarian follicles. DGKη1 was distributed in the oviductal epithelium of the ovary and the luminal epithelium of the uterus. Intriguingly, DGKη3 was strongly expressed in the secondary spermatocytes and round spermatids of the testis. DGKκ was distributed in the primary and secondary spermatocyte of the testis.ConclusionThese results indicate that the expression patterns of the type II DGK isoforms δ2, η1, η3 and κ differ from each other, suggesting that these DGK isoforms play specific roles in distinct compartments and developmental stages of the reproductive organs, especially in the processes of spermatogenesis and oocyte maturation.