People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.

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Petrobactin is a bis-catecholate, alpha-hydroxy acid siderophore produced by the oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus. The Fe(III)-complexed form of petrobactin is photoreactive in natural sunlight, mediated by the Fe(III)-citrate moiety. The reaction results in decarboxylation of the petrobactin ligand and reduction of Fe(III) to Fe(II). This report is one of the first to show the photoreactivity of Fe(III)-siderophores mediated by the ferric ion-alpha-hydroxy acid group. The demonstration of light-mediated decarboxylation of an Fe(III)-siderophore complex raises questions about a possible functional role for photoreactivity in siderophore-mediated iron uptake.

PDE3A functionally and physically interacts with CFTR. Inhibition of PDE3A generates compartmentalized cAMP, which further clusters PDE3A and CFTR into microdomains at the plasma membrane of epithelial cells and potentiates CFTR channel function. Our findings provide insights into the important role of PDE3A in compartmentalized cAMP signaling.

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The pore-forming subunit of the large-conductance Ca 2+ -dependent K + (Slo1) channel is encoded by one gene. However, the functional properties of Slo1 channels are diverse in part because of their numerous regulatory mechanisms including posttranslational modification and alternative splicing. In particular, multiple splice variants of the pore-forming subunit have been reported but their significance is only beginning to be elucidated. Here we examined the cell biological properties of the three common C-terminal isoforms that differ in the last 8 (Slo1_ERL and Slo1_VYR) or 61 residues (Slo1_DEC). We found that Slo1_DEC, the longest isoform, shows dramatically reduced surface expression compared to that of Slo1_ERL or Slo1_VYR. Immunocytochemistry revealed that a large fraction of Slo1_DEC remains localized in endoplasmic reticulum (ER). Using a GST fusion protein containing the Slo1_DEC-specific sequence, affinity purification was carried out to isolate interacting proteins. The identified proteins include protein phosphatase 2A (PP2A-A), actin, and tubulin. The PP2A-A interaction is specific to Slo1_DEC and causes a significant reduction of phosphorylation in Slo1_DEC but not Slo1_ERL or Slo1_VYR. The results together support the notion that Slo1_DEC nucleates isoform-specific protein complexes and possesses a cis element(s) for regulating trafficking of the Slo1 channels.

Culture of the oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus gave the known siderophore petrobactin (1) and the new metabolite petrobactin sulfonate (2), the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structure of petrobactin sulfonate was elucidated from spectral data, resulting in a revision of the NMR assignments of petrobactin.

The S4 transmembrane segment is the primary voltage sensor in voltage-dependent ion channels. Its movement in response to changes in membrane potential leads to the opening of the activation gate, which is formed by a separate structural component, the S6 segment. Here we show in voltage-, Ca 2؉ -, and Mg 2؉ -dependent, large conductance K ؉ channels that the S4 segment participates not only in voltage-but also Mg 2؉ -dependent activation. Mutations in S4 and the S4-S5 linker alter voltagedependent activation and have little or no effect on activation by micromolar Ca 2؉ . However, a subset of these mutations in the C-terminal half of S4 and in the S4-S5 linker either reduce or abolish the Mg 2؉ sensitivity of channel gating. Cysteine residues substituted into positions R210 and R213, marking the boundary between S4 mutations that alter Mg 2؉ sensitivity and those that do not, are accessible to a modifying reagent [sodium (2-sulfonatoethyl)methane-thiosulfonate] (MTSES) from the extracellular and intracellular side of the membrane, respectively, at ؊80 mV. This implies that interactions between S4 and a cytoplasmic domain may be involved in Mg 2؉ -dependent activation. These results indicate that the voltage sensor is critical for Mg 2؉ -dependent activation and the coupling between the voltage sensor and channel gate is a converging point for voltage-and Mg 2؉ -dependent activation pathways.