The neuronal p35 activator of Cdk5 is a novel F-actin binding and bundling protein

The neuronal Cdk5 activator p35 is involved in a multitude of neuronal activities, including cytoskeletal organization. We show here that p35 directly interacts with filamentous actin (F-actin) but not with monomeric actin (G-actin). Through binding, p35 induces the formation of actin bundles and stabilizes F-actin against dilution-induced depolymerization. p35 forms intermolecular self-associations, suggesting that p35 cross-links actin filaments into bundles via its intermolecular self-association. p35 dimerization and association with F-actin occur at the N-terminal region that is absent in the calpain-cleaved product p25, indicating that such p35 properties are lost by its truncation induced under neurotoxic conditions. Using p35 phosphorylated by Cdk5 and a mutational approach, we demonstrate that the phosphorylation of p35 promotes its homodimerization and p35-induced formation of F-actin bundles. In addition, the phosphorylation regulates p35 distribution to microtubule and actin cytoskeletons. Together, these observations define a novel function for p35 in cytoskeletal regulation.     

Interaction of DISC1 with the PTB domain of Tensin2

The gene for Disrupted-in-Schizophrenia 1 (DISC1) is amongst the most significant risk genes for schizophrenia. The DISC1 protein is an intracellular scaffolding molecule thought to act an important hub for protein interactions involved in signalling for neural cell differentiation and function. Tensin2 is an intracellular actin-binding protein that bridges the intracellular portion of transmembrane receptors to the cytoskeleton, thereby regulating signalling for cell shape and motility. In this study, we probed in molecular detail a novel interaction between DISC1 and Tensin2. Western blot and confocal microscopic analyses revealed widespread expression of both DISC1 and Tensin2 proteins throughout the mouse brain. Furthermore, we have developed novel anti-DISC1 antibodies that verified the predominant expression of a 105-kDa isoform of DISC1 in the rodent brain as well as in human cells. In the mouse brain, both proteins showed region-specific expression patterns, including strong expression in the pyramidal cell layer of the hippocampus and dentate gyrus. DISC1–Tensin2 colocalisation was most clearly observed in the Purkinje cells of the mouse cerebellum. Biochemical coimmunoprecipitation experiments revealed an interaction between endogenous DISC1 and Tensin2 proteins in the mouse brain. Further pulldown studies in human cells using Myc-tagged Tensin2 constructs revealed that DISC1 specifically interacts with the C-terminal PTB domain of Tensin2 in a phosphorylation-independent manner. This new knowledge on the DISC1–Tensin2 interaction, as part of the wider DISC1 interactome, should further elucidate the signalling pathways that are perturbed in schizophrenia and other mental disorders.     

Pharmacological studies of a new analgesic,dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride,in experimental animals

Summary dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.     

Pharmacological studies of a new analgesic, dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride, in experimental animals.

dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.     

2-Amino-6-[(1'R,2'S)-1',2'-dihydroxypropyl]-3-methyl-pterin-4-one,a biologically active metabolite from the anthozoanAstroides calycularis Pallas

Summary 2-Amino-6-[(1'R,2'S)-1',2'-dihydroxypropyl]-3-methyl-pterin-4-one (1) has been isolated from the marine anthozoanAstroides calycularis; its structure was illustrated by spectral analyses including 2D-NMR and by partial synthesis.1 appears to possess cell-growth inhibiting activity.29 December 1986Work supported by C.N.R. (Progetto Finalizzato Chimica Fine e Secondaria) and by Ministero Pubblica Istruzione Italy. — Acknowledgments. Mass spectral data were provided by Servizio di Spettrometria di massa del C.N.R. e dell'Università di Napoli. The assistance of the staff is gratefully appreciated. Finally we would like to thank Prof. C. Pietropaolo for supplying chick embryo fibroblasts.     

Effect of imazalil (1-(2-(2,4-dichlorophenyl)-2-(2-propenyloxy) ethyl)-1H-imidazole) on biosynthesis of ergosterol in Penicillium expansum Link]

Imazalil is a new fungicide effective against Penicillium molds on fruits after harvest. This compound inhibits ergosterol biosynthesis in mycelia of Penicillium expansum. The accumulation of 24--methylenedithydrolanosterol, obtusifoliol and 14 alpha-methyl-delta 8, 24(28)-ergostadienol in treated fungi suggests that imazalil blocks sterol C--14 demethylation.     

Antihypertensive agents III. Synthesis and antihypertensive activity of 3-[4-(p-fluoro-phenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-[1-(2-hydroxyethyl)-5-methyl-4-pyrazolyl]-1-propanone

Zusammenfassung 3-[4-(p-Fluorphenyl)-1,2,3,6-te-trahydro-1-pyridyl]-1-[1-(2-hydroxyaethyl)-5-methyl-4-pyrazolyl]-1-propanon (I, CIBA 4416/B-Go) senkt bei normotonischen und hypertonischen Tieren den Blutdruck. Die Drucksenkung kann hauptsächlich auf die periphere Vasodilatation sowie auf die Vasomotorenzentren bezogen werden. Ausserdem wirkt CIBA 4416/B-Go adrenolytisch.

---

Previous paper:V. P. Arya, R. S. Grewal, C. L. Kaul, S. P. Ghate, D. V. Mehta andT. George, J. Pharm. Sci.58, 432 (1969).Contribution No. 243 from CIBA Research Centre.     

The efficacy of a novel compound, (E)-1-(4′-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene againstTrypanosoma cruzi in mice

Summary The biological properties of a novel compound 353C with high activity againstTrypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C had a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.     

The effect of terbutaline (PINN) 1-(3.5-dihydroxyphenyl)-2-(t-butylamino)-ethanol on the choledochoduodenal sphincter

Zusammenfassung Die- Rezeptoren vom Sphinkter von Oddi werden durch Terbutalin selektiv stimuliert.     

Ar1-5 and Ar2-6 aryl participation in ionic and free radical processes

Zusammenfassung Die Beteiligung von Arylgruppen in Solvolysen von 4-Aryl-1-butylhalogeniden und Arylsulfonaten sowie in Reaktionen von freien 4-Aryl-1-butyl-radikalen wird diskutiert. Bei geeignet methoxylierten oder hydroxy-lierten 4-Aryl-1-butylverbindungen kann die Formolyse entweder mit Ar₁-5-oder Ar₁-6-Arylbeteiligung verlaufen. Dies führt zur Bildung von Tetralin. Da bei Ar₁-5-Beteiligung ein Spirocarboniumion entsteht, in welchem entweder C oder C der ursprünglichen Butylseitenkette wandern kann, ist es möglich, dass ein anderes Tetralin geformt wird als auf dem direkteren Ar₂-6-Weg. Als Beispiel dient die Formolysenreaktion von 4-p-Anisyl-4-methyl-1-pentylbrombenzolsulfonat.

---

---

Research supported by the Office of Naval Research. — Research sponsored by the Office of Ordnance Research, U. S. Army.     

The inhibiting actions on poliovirus multiplication of 1-alkyl-2-(α-methoxybenzyl)benzimidazoles

Zusammenfassung 1-Alkyl-2-(-methoxybenzyl)-benzimidazole hemmt die Vermehrung des Poliovirus der Arten 1, 2 und 3, wobei das 1-Propyl-Derivat die grösste Wirkung hat.

---

---

The research is supported by the National Fund for Research into Poliomyelitis and other Crippling Diseases.     

Recombinant synthesis of mouse Zn3-β and Zn4-α metallothionein 1 domains and characterization of their cadmium(II) binding capacity

Genetic engineering, coupled with spectro scopic analyses, has enabled the metal binding proper ties of the α and β subunits of mouse metallothionein 1 (MT) to be characterized. A heterologous expression system in E.coli has led to high yields of their pure zinc-complexed forms. The cadmium(II) binding properties of recombinant Zn₄-αMT and Zn₃-βMT have been studied by electronic absorption and circular dichroism. The former binds Cd(II) identically to α fragments obtained from mammalian organs, showing that the recombinant polypeptide behaves like the na tive protein. Titration of Zn₃-βMT with CdCl₂ results in the formation of Cd₃-βMT. The addition of excess Cd(II) leads to Cd₄-βMT which, with the extra loading of Cd(II), unravels to give rise isodichroically to Cd₉-βMT. The effect of cadmium-displaced Zn(II) ions and excess Cd(II) above the full metal occupancy of three has been studied using Chelex-100. The Cd₃-βMT species is stable in the presence of this strong metal-chelating agent. Received 20 May 1997; received after revision 7 July 1997; accepted 9 July 1997