The vacuolar-type H؉ -ATPase (V-ATPase) translocates protons across membranes. Here, we have identified a mouse cDNA coding for a fourth isoform (a4) of the membrane sector subunit a of V-ATPase. This isoform was specifically expressed in kidney, but not in the heart, brain, spleen, lung, liver, muscle, or testis. Immunoprecipitation experiments, together with sequence similarities for other isoforms (a1, a2, and a3), indicate that the a4 isoform is a component of V-ATPase. Moreover, histochemical studies show that a4 is localized in the apical and basolateral plasma membranes of cortical ␣-and ␤-intercalated cells, respectively. These results suggest that the V-ATPase, with the a4 isoform, is important for renal acid/base homeostasis. A ubiquitous vacuolar-type Hϩ -ATPase (V-ATPase) 1 translocates protons across membranes utilizing the energy of ATP hydrolysis (for reviews, see Refs. 1-5). The organellar acidic pH generated by V-ATPase is responsible for various processes including zymogen activation, receptor-mediated endocytosis, macromolecule degradation, and protein sorting. The enzyme is also found in plasma membranes, where it transports protons outside cells such as osteoclasts (6, 7), renal-intercalated cells (8), and epithelial cells of the seminal duct and bladder (9, 10).V-ATPase has a membrane peripheral V 1 sector for ATP hydrolysis and an integral V o for proton translocation (1-5). The V o sector consists of at least five subunits (a, c, cЈ, cЉ, and d) (11). Subunit a is the largest (116 kDa) of the V-ATPase subunits, and its isoforms have been found in yeast (12), chicken (13), mouse (7, 14, 15), cow (16, 17), and human (18). These isoforms exhibit different distributions in organelles and tissues. Yeast isoforms (Vph1p and Stv1p) are localized in vacuoles and Golgi/endosomes, respectively (12). Three isoforms (a1, a2, and a3) have been found previously in mammals (7, 14 -18). These isoforms may be important for the localization of V-ATPase in various organelles or plasma membranes.In this study, we have isolated a mouse cDNA coding for a fourth isoform (a4) of V-ATPase subunit a. Isoform a4 exhibits high similarities with the a1, a2, and a3 isoforms and is expressed exclusively in kidney. Furthermore, a4 was localized immunochemically in the apical and basolateral plasma membranes of cortical ␣-and ␤-intercalated cells, respectively. These results suggest that the V-ATPase with the a4 isoform is a kidney-specific proton pump important for acid/base homeostasis.

We developed a quantitative assay for Caenorhabditis elegans avoidance behavior. This was then used to demonstrate that the worm moved away from toxic concentrations of Cd2+ and Cu2+, but not Ni2+, all ions that prevented development from larval to adult stages. Mutants that have structural defects in ciliated neurons (che-2 and osm-3) as well as worms with three laser-operated neurons (ADL, ASE, and ASH), showed no avoidance behavior from Cd2+ and Cu2+. These results suggest that the avoidance from Cd2+ and Cu2+ are mediated through multiple neural pathways including ADL, ASE, and ASH neurons. We hypothesize that the three sensing neurons provide increased accuracy of the sensory response and a survival advantage in the natural environment of the worm.

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Psychiatric disorders have clear heritable risk. Several large-scale genome-wide association studies have revealed a strong association between susceptibility for psychiatric disorders, including bipolar disease, schizophrenia, and major depression, and a haplotype located in an intronic region of the L-type voltage gated calcium channel (VGCC) subunit gene CACNA1C (peak associated SNP rs1006737), making it one of the most replicable and consistent associations in psychiatric genetics. In the current study, we used induced human neurons to reveal a functional phenotype associated with this psychiatric risk variant. We generated induced human neurons, or iN cells, from more than 20 individuals harboring homozygous risk genotypes, heterozygous, or homozygous non-risk genotypes at the rs1006737 locus. Using these iNs, we performed electrophysiology and quantitative PCR experiments that demonstrated increased L-type VGCC current density as well as increased mRNA expression of CACNA1C in induced neurons homozygous for the risk genotype, compared to non-risk genotypes. These studies demonstrate that the risk genotype at rs1006737 is associated with significant functional alterations in human induced neurons, and may direct future efforts at developing novel therapeutics for the treatment of psychiatric disease.

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These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.

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