The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways

Cyclic adenosine 3', 5'-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs) but also activates certain ion channels and guanine nucleotide exchange factors (Epacs). Metabolism of cAMP is catalysed by phosphodiesterases (PDEs). Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.     

Mutations in dynamin 2 cause dominant centronuclear myopathy

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.     

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

We identified the gene underlying Marinesco-Sj?gren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sj?gren syndrome.     

Divergent effects of theophylline on adenylate cyclase preparations from guinea-pig heart and lung

Zusammenfassung Theophyllin verringert die Aktivität der Adenyl-Cyclase (AC) in der plasmamembranreichen Fraktion der Meerschweinchenlunge in Konzentrationen von 6–10 mM; es hat dagegen keinen Einfluss auf die Aktivität der AC in Meerschweinchenherzen. Diese Resultate weisen darauf hin, dass in verschiedenen Geweben geringe Unterschiede in der Enzym-Katalyse bestehen können.     

Paramagnetism of human serum proteins demonstrated by two-stage electromagnetophoresis

Zusammenfassung Normale Serumproteine wurden mittels zweistufiger Elektromagnetophorese in Polyacrylamidgel, einer neuen Technik, aufgetrennt, wobei die Trennung auf Grund der paramagnetischen Eigenschaften der einzelnen Proteine erfolgt.

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Supported by William Beaumont Hospital Research Institute in Affiliation with the Research Laboratories, General Motors Corporation and Department of Pathology, School of Medicine, Wayne State University.     

Induction of developmental anomalies in mice by maternal stress

Summary The short-time restraint of pregnant mice on day 8 of gestation led to a significant increase of the anomaly rate in fetuses. This effect may be due to stress factors of endocrine origin.The technical assistance of Mrs E. Frei is gratefully acknowledged. Supported by the Swiss National Foundation for Scientific Research.     

Influence of age on the plasma hormonal iodine response to thyrotropin injection in young calves]

The influence of age upon the increase in plasma hormonal iodine level following an intravenous injection of bovine TSH (0.2 USP units/kg) was studied in young jersey calves. The response to TSH increased between birth and the 7th day, then decreased regularly until the end of the third month. Reasons for these variations are discussed according to some results obtained following TSH injections.     

Chronic split brain stem preparation: Effect on the sleep-waking cycle

Résumé La préparation du chat à tronc cérébral dédoublé peut être conservée pendant plusieurs mois en bon état. Elle se caractérise par un très haut niveau de vigilance avec réduction du sommeil lent et du sommeil rapide. Lorsque la section sagitale médiane est très étendue, alternativement chaque hemisphère peut présenter un tracé lent tandis que l'autre hemisphère présente un tracé rapide; cette asynchronie peut durer jusqu'à 25 min.

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A preliminary paper has been presented at Ass. for Psychophysiological Study of Sleep, Gainesville, Florida, March, 1966.