Soluble factors, NSF and SNAPs, are required at many membrane fusion events within the cell. They interact with a class of type II integral membrane proteins termed SNAP receptors, or SNAREs. Interaction between cognate SNAREs on opposing membranes is a prerequisite for NSF dependent membrane fusion. NSF is an ATPase which will disrupt complexes composed of different SNAREs. However, there is increasingly abundant evidence that the SNARE complex recognised by NSF does not bridge the two fusing membranes, but rather is composed of SNAREs in the same membrane. The essential role of NSF may be to prime SNAREs for a direct role during fusion.

We suggest that these observations are most compatible with a model for transit through the Golgi in which anterograde cargo is carried in cisternae, the enzymatic composition of which changes with time as Golgi resident enzymes are delivered in retrograde transport vesicles [4].

We recently independently identified STX17 as a novel Ras-interacting protein, but immunohistochemical studies suggested that STX17 is localized to the nucleus in normal pancreatic ductal pithelial, acinar, and islet cells in contrast to previous reports of cytoplasmic localization, albeit in other cell types. Therefore, we have conducted a more thorough survey of various human and mouse tissues to better establish the expression pattern of STX17 in different tissues and cell types. Although RT-PCR experiments demonstrate ubiquitous expression of STX17, closer examination by immunohistochemistry reveal that STX17 expression is limited to certain cell types. Furthermore, in contrast to the cytoplasmic localization previously reported in a limited number of cell types, we find that in many other cell types, Syntaxin-17 can be found in the nucleus. Finally, we demonstrate that in human hepatocellular carcinoma cell lines, STX17 localization is altered relative to normal hepatocytes although the localization of STX17 differs even between these established human cancer cell lines and fresh human hepatocellular carcinoma cells, emphasizing the caution that must be exercised in drawing conclusions from data gathered in cell lines. The sequence divergence of STX17, the unexpected nuclear localization of STX17 in many cell types, and the altered localization of STX17 in malignant cells argue for a novel function of Syntaxin-17 distinct from its hypothesized role in mediating membrane fusion events.

A fundamental molecular component of neural connectivity is the SNARE (SNAP receptor) protein complex, which consists of three proteins, syntaxin, SNAP-25 and VAMP. Under appropriate conditions, the SNARE complex can be formed in vitro. To investigate the hypothesis that dysregulation of SNARE proteins or their interactions could be abnormal in severe mental disorders, the three SNARE proteins and the complex were studied in post-mortem anterior frontal cortex homogenates. An ELISA was used to quantify SNARE protein immunoreactivities in cortical homogenates from four groups: patients with schizophrenia who died of causes other than suicide (n = 6), patients with schizophrenia and suicide (n = 7), patients with depression and suicide (n = 11), and controls (n = 11). Differences between groups in patterns of SNARE protein immuno-reactivities were demonstrated [Wilks' Lambda F(9,68) = 3.57, P = 0.001]. Protein-by-protein analyses indicated a significant reduction in SNAP-25 immunoreactivity in the schizophrenia non-suicide group [28 decrease relative to controls, F(3,31) = 6.45, P = 0.002, Student-Newman-Keuls test, P < 0.01]. The intercorrelations between SNARE protein and synaptophysin immunoreactivities were high in controls, but lower in the other groups, further indicating disturbances in relationships between these proteins. The extent of SNARE complex formation in vitro was studied using immuno-blotting. Significant differences related to group membership were observed for the SNARE complexes identified by SNAP-25 [Wilks' Lambda F(3,31)=4.76, P=0.008] and by syntaxin immunostaining [Wilks' Lambda F(3,31)=9.16, P=0.0002]. In both groups with suicide as a cause of death, relatively more SNAP-25 and syntaxin was present in the heterotrimeric SNARE complex than in other molecular forms. These abnormalities in the SNARE complex could represent a molecular substrate for abnormalities of neural connectivity in severe mental disorders [8].

Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. RESULTS: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2)=5.898; df=1; p=.015, family-based association test [FBAT] z=2.280, p=.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n=430; z(c)=2.859; p=.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP [9].

"Retroviral-related amplicons were used in modified RDA to identify four sequences from affected members of three pairs of monozygotic twins discordant for schizophrenia. One sequence (schizophrenia associated retrovirus, SZRV-1, GenBank Accession No. AF135487) is characterized here. It is similar to two known sequences of retroviral origin: multiple sclerosis-associated retrovirus, MSRV (GenBank Accession No. AF009668), and ERV-9 (GenBank Accession No. S77575)." [11]

Human erythrocytes contain a nicotinamide adenine dinucleotide phosphate (NADP[H])-binding protein, FX, whose levels are significantly increased in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals bearing the mediterranean variant of G6PD. Elucidation of the still unknown biologic functions of FX was approached by means of amino acid sequencing of its 25 tryptic peptides. Searching in the EMBL data bank allowed identification of extensive homology between these tryptic peptides and all sequence-aligned regions encompassing the complete structure of a putative protein encoded by the P35B gene in the mouse. This gene, which differs from the normal allele by a point mutation, has been previously cloned from a tum- variant of the murine tumor cell line P815, so defined because it is associated with low tumorigenicity compared with the progenitor P815." [12]

"the enzyme responsible for the last step of the major metabolic pathway resulting in GDP-L-fucose synthesis from GDP-D-mannose in procaryotic and eucaryotic cells. Specifically, purified FX apparently catalyzes a combined epimerase and NADPH-dependent reductase reaction, converting GDP-4-keto-6-D-deoxymannose to GDP-L-fucose. This is the substrate of several fucosyltranferases involved in the correct expression of many glyconjugates, including blood groups and developmental antigens." [18]

"A relationship between psychiatric disorder and G6PD deficiency is to be searched in the bipolar spectrum, particularly among patients with a history of acute episodes with psychotic and/or catatonic symptoms or with transient confusion." [19]

"Reduced glucose uptake will disrupt production of glutamate - functionally similar to the schizophrenia-like syndrome produced by PCP, a glutamate antagonist. In the longer term, reduced neuronal growth and poor synaptic contacts will produce chronic cognitive difficulties and perpetuate acute symptoms. A backlog effect due to reduced brain uptake of glucose would produce systemic hyperglycaemia observed in drug naive subjects. Rat studies have shown that clozapine and similar compounds block GLUT proteins in the brain and peripherally, more so than selective dopamine blockers. By blocking GLUT proteins, clozapine would break malfunctioning circuits, resulting in the disappearance of cognitive and perceptual symptoms. Unfortunately, these drugs would also raise systemic glucose levels, increasing the risk of diabetes, as observed in longer term studies of clozapine in particular. We summarise potentially useful research strategies, including studying the genotype of GLUT proteins with respect to schizophrenia phenotypes, activation studies involving fMRI using deoxyglucose as a substrate, and investigating clinical features of schizophrenic patients prior to and following treatment for co-existing diabetes." [22]

"Structural studies of the peptides in lipid bilayers performed by Fourier transform infrared spectroscopy indicated mixtures of alpha-helical and beta-sheet conformations. In isotropic solution, circular dichroism spectroscopy showed the peptides to exist in a concentration-dependent equilibrium of alpha-helical and beta-sheet structures. Interestingly, the fusogenic activity decreased with increasing stability of the alpha-helical solution structure for a panel of variant peptides." [24]