Internalization of polypeptide hormones and receptor recycling

Conclusion The insulin receptor is an integral protein of the plasma membrane of the cell. It is composed of two subunits: an subunit, which binds the hormone, and a subunit which is a tyrosine specific protein kinase capable of undergoing autophosphorylation. These independent subunits are synthesized by way of a higher molecular weight single chain precursor and thus are the product of a single gene^{29, 49, 85} localized to chromosome 19^{29, 91}. Assuming that the insulin receptor is synthesized in the same fashion as other integral membrane glycoproteins, then the nucleus, the rough endoplasmic reticulum, and the Golgi apparatus are involved in its biosynthesis. Further, there must be some form of transport of the mature receptor subunits to the plasma membrane where they are inserted.By contrast, the endocytotic route involves coated pits, coated vesicles, large clear vesicles or endosomes, multivesicular bodies and other lysosomal forms. In addition, it is possible that some other as yet unidentified organelle is involved in recycling (fig. 8). At the present time, with respect to the insulin receptor, the biosynthetic pathway and the endocytotic pathway appear to be separate. Further, it does not appear that either pathway, i. e. synthesis or endocytosis, exerts a regulatory function over the other.     

New phytotoxic butenolides produced bySeiridium cardinale,the pathogen of cypress canker disease

Summary Two new butenolides, seiridin andiso-seiridin, were isolated from culture filtrates ofSeiridium cardinale, the pathogen of cypress canker, a destructive disease ofCupressus and relatedConiferae These metabolites were characterized as 3-methyl-4-(2-hydroxyheptyl)-2(5H)-furanone and its 4-(3-hydroxyheptyl) isomer, respectively. Chlorotic, and necrotic symptoms were produced on leaves of either host or non-host test plants by absorption of 0.3 mg/ml solutions of either compound. These also showed antibacterial activity.This study was supported in part by the National Research Council, Rome (special ad hoc project Chimica fine e secondaria) and in part by the Ministry of Education, Rome.     

Suitability of urethane anesthesia for physiopharmacological investigations in various systems Part 1: General considerations

Summary The suitability of urethane anesthesia for physiopharmacological investigations is reviewed. Total dose administered and route of administration are recognized as factors having a great influence on both resting parameters and biological responses to drugs. A peculiar characteristic of urethane is represented by its ability to induce a surgical plane of anesthesia without affecting neurotransmission in various subcortical areas and the peripheral nervous system. This makes urethane a suitable general anesthetic for studying neural function in both central and peripheral nervous systems and accounts for the preservation of a number of reflex responses in urethane-anesthetized animals.     

Bromocriptine-induced removal of endoplasmic membranes from prolactinoma cells

Summary Adenomatous prolactin cells lose 39% of their cytoplasm volume within 7 days after the beginning of bromocriptine treatment. A simultaneous reduction of the rough-surfaced endoplasmic reticulum and the Golgi apparatus occurs. Their membranes are removed by rapid transport along the secretory pathway to the cell surface and to lysosomal destruction.We thank Prof. E. del Pozo, Sandoz Ltd, Basle, for the generous gift of injectable bromocriptine, Prof. E.R. Weibel, Dept. of Anatomy, University of Bern, for his technical advice, Dr U. Helfenstein, Institute of Biostatistics, University of Zürich, for his help in the statistical evaluation of the results and the EMDO-Foundation, Zürich, for financial support.     

Novel rearrangement of purines

6-Trichloromethyl-9-methylpurine (1) rearranges to 6-dichloromethyl-9-methyl-8-oxopurine (2) in aqueous mild acidic solution. The rearrangement is rationalized in terms of a reaction involving protonation, covalent hydration, prototropic equilibrium and/or a hydride transfer. An alternative mechanism involving a "positive' halogen compound and hypochlorous acid as an intermediary is also proposed. Compound 1 condenses with 4,5-diaminopyrimidine to give the purine-pyrimidine Schiff base pair 4.     

Antidiuretic effects of oxytocin in the Brattleboro rat

Summary The antidiuretic activity of oxytocin (OT) was measured in Brattleboro rats with congenital diabetes insipidus. A dose dependent antidiuretic response was found in animals receiving chronic infusions of 0.1 g/h, 1.0 g/h, and 5 g/h of OT. OT infused at the rate of 5 g/h over a 7-day period completely reversed the symptoms of diabetes insipidus. The results support the concept that OT serves as a weak agonist of vasopressin at the level of the kidney and at pharmacological levels exhibits antidiuretic activity.     

Determination of certain physical and chemical characteristics of the activating serum factor from preparturient women and women with habitual abortions

Summary Follow-up investigation of the blood sera from preparturient women and women with habitual, abortions showed the presence of a factor which has an activating effect on smooth muscle preparations because it causes the release of prostaglandins. Gel-chromatographic counter flow separation and microelectrophoresis of the blood sera have shown that the isolated serum factor is a water soluble glycopeptide with a molecular weight of about 2000.     

Selective protection of cells against X-irradiation. Isoproterenol protects only those cells that possesβ-adrenoreceptors

Summary In mixed culture of Chinese hamster fibroblatst, clone 431, and transformed murine L fibroblasts, clone B-82, isoproterenol was found to protect only 431 cells against ionizing radiation. It was shown that 431 cells, in contrast to B-82 cells, possess-adrenoreceptors, and the radioprotective effect of isoproterenol can be realized only if this agent interacts with-adrenoreceptors coupled with the cAMP system. Since malignization often causes the disappearance of-adrenergic and other hormone receptors, the combined culturing and irradiation of the cells studied can be regarded as a model of the growth of malignant cells (B-82) among normal tissue cells (431 cells) under conditions of radiation therapy. A possibility of selective protection against radiation damage of normal tissue cells, with retention of the former radiosensitivity of tumor cells, is discussed.     

AnAnolis skin melanophore assay suitable for photoaffinity labeling studies with α-MSH

Summary Visual determination of MSH-induced pigment migration in melanophores of small pieces ofAnolis carolinensis skin is standardized by first measuring photoelectrometrically the change in reflection/transmission of the whole dorsal skin in response to different hormone concentrations. This method allows the rapid and precise recording of time-response curves after photoaffinity labeling of MSH receptors or of dose-response curves of large series of synthetic compounds.Acknowledgments. We wish to thank Ms V. Jäggin, Ms C. Schulthess and Ms G. van Hees for excellent technical assistance, Dr. R. Andreatta, Ciba-Geigy AG, Basel, for his generous gift of -MSH and Prof. A Pletscher for his continuous interest. This work was supported by the Swiss National Science Foundation.     

Internal interactions within the human circadian system: the masking effect

Summary In the realm of human circadian rhythms, the masking effect is defined as the change in the course of deep body temperature induced by changes in the degree of physical activity, or by the alteration between sleep and wake. This effect is particularly obvious during internal desynchronization where the rhythms of deep body temperature, and the sleep-wake sleep-wake sleep cycle — i.e. one of the masking factors — run with different periods.Every sleep onset is accompanied by a rapid drop, and wake onset by a rapid rise in deep body temperature, each one with an overshoot of about 50% of the steady state variations. When rhythms are calculated, with the dominant temperature period as the screening period, exclusively from data obtained during sleep episodes, on the one hand, and from those obtained exclusively during wake, on the other, two average cycles emerge: the sleep temperature curve and the wake temperature curve. Both run in parallel but are separated by the masking effcct. As derived from many experiments, the mean masking effect amounts to 0.28±0.06°C. The masking effect also depends to some extent on the phase of the temperature rhtthm; it is larger than average around the temperature maximum and during the descending phase of the temperature cycle, where the alertness commonly is highest and the probability to sleep, in general, and the REM sleep propensity, in particular, are smaller than average. This also can be interpreted to indicate that the sleep temperature curve is phase advanced relative to the wake temperature curve; this, on the average, by 0.9±0.3 h.If the individually determined amount of masking is added to the temperature data obtained during sleep, or substracted from the temperature data obtained during wake, a temperature curve emerges that can be though of as being purified of the masking effect. Analyses of this artificial curve allow estimation of that part of the internal interactions uninfluenced by the masking effect. On the average, about half of the amount of interaction between the rhythm of sleep-wake and that of deep body temperature is explained by the masking effect, whereas the other half is oscillatory interaction. Both types of interaction are inherent and inseparable parts of the circadian clock mechanism, as can be deduced from model considerations.