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Fortschritte der molekularen Endokrinologie

Progress in molecular endocrinology

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Summary

Recent advances towards an understanding of the molecular basis of hormone action are described. Main attention is focussed on β-adrenergic action and on signal transmission from β-adrenoceptor to adenylate cyclase including signal amplification.

Molecular properties of guanine nucleotide binding amplifier proteins are recapitulated. The hormone-sensitive membrane-bound adenylate cyclase system is characterized as a multicomponent system made up of several heterologous subunits that reversibly interact with each other by means of association-dissociation reactions. These properties are exemplified by the role of inhibitory and stimulatory guanine nucleotide proteins which communicate with each other through the intervention of β,γ-subunits which are common to both. Once a second messenger such as cyclic AMP (cAMP) is formed, in response to a stimulatory hormone, a cascade of reactions is triggered which profoundly change cellular metabolism and are responsible for pleiotropic hormone action. For example, the group of hormones whose action is transmitted by means of the second messenger cAMP sets in motion a series of protein phosphorylation reactions, starting with the activation of a cAMP-dependent protein kinase and involving a series of specific protein kinases and phosphoprotein phosphatases and inhibitor and modifier proteins. The activity of several key enzymes controlling cell metabolism and substrate flux through metabolic pathways is regulated by phosphorylation-dephosphorylation reactions as are ion-channel forming proteins and proteins with other important cellular functions.

Recent findings on signal transmission chains liberating intracellular calcium are summarized. Calcium-releasing hormones actvia activation of polyphosphatidylinositolphosphodiesterase which cleaves phosphatidylinositol 4,5-bis-phosphate to diacylglycerol and inositoltrisphosphate. Diacylglycerol in turn activates protein kinase C, whereas inositoltrisphosphate is a novel second messenger which liberates calcium from intracellular stores perhaps by binding to a specific receptor protein. Of special interest is the role of oncogene-coded proteins in polyphosphatidylinositol metabolism. Cellular and viral “ras” genes deserve special attention, because they code for GTP-binding proteins which have properties similar to those of the GTP-binding proteins of the adenylate cyclase system, although the “ras” proteins with molecular weight 21 kDa do not act as transducers in the adenylate cyclase system. A hypothetical scheme for a possible role of oncogenic “ras” proteins in uncontrolled production of inositoltrisphosphate and diacylglycerol is presented.

Striking similarities between the hormonally activated adenylate cyclase system and the rhodopsin activated amplification cascade have led to the assumption that GTP binding and hydrolyzing amplifier proteins which occur in several biological systems belong to a class of proteins, very old from an evolutionary standpoint, which fulfil their biological function by means of conformational transitions made possible by reversible association-dissociation reactions. The argument for GTP binding proteins as evolutionary relatives is supported by the fact that all these proteins are targets for ADP-ribosyltransferase reactions catalyzed by pathogenic toxins. In the case of the adenylate cyclase system the action of cholera toxin and ofBordetella pertussis toxin on activating (G s ) and inhibiting (G i ) guanine nucleotide binding proteins are pertinent. These toxin actions can explain, at least in part, some of the pathological sequelae ofBordetella pertussis and cholera toxin infections. In the case of theBordetella pertussis infection the ADP-ribosylated, covalently modified inhibitory GTP-binding protein (G i ) becomes nonfunctional so that adenylate cyclase is no longer under the inhibitory influence. This in turn leads to increased, uncontrolled cAMP production and to pathological consequences such as hypoglycemia.

Cholera toxin modifies the stimulatory GTP-binding protein (G s ) and prevents the termination reaction due to GTP hydrolysis. Consequently, Gs becomes persistently activated, leading in turn to a prolonged and persistent activation of adenylate cyclase. Differences in the action of these and other toxins result from different substrate specificities and from differences in cellular targets as well, because only certain cell types have a toxin receptor. Thus, the comprehension of the hormonal signal transmission chain from β-adrenoceptor to adenylate cyclase on a molecular level has provided, as a welcome side product, a satisfactory understanding of the molecular mechanisms of the action of some toxins and of the pathophysiological consequences resulting from infection of man with the toxin-producing, pathogenic infectious agents.

An important application in neurobiology of the new findings concerning hormonal signal transmission chains is the molecular analysis of the learning process in the marine snailAplysia californica and its relationship to neurotransmitter-activated signal transmission pathways.

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Authors and Affiliations

  1. Physiologisch-Chemisches Institut der Julius-Maximilians-Universität Würzburg, Germany

    E. J. M. Helmreich

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Vortrag beim Fest-Kolloquium zu Ehren von Professor Dr. med. Walter Seitz, vormals Direktor der Medizinischen Universitäts-Poliklinik, anläßlich seines 80. Geburtstages, 23. Oktober 1985. Diesen Beitrag widmet der Autor Walter Seitz in Dankbarkeit und Freundschaft.

Die Arbeiten des Autors werden gefördert im SFB 176 der Universität Würzburg, durch die Thyssen-Stiftung und den Fonds der Chemischen Industrie e.V.

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Helmreich, E.J.M. Fortschritte der molekularen Endokrinologie. Klin Wochenschr 64, 669–681 (1986). https://doi.org/10.1007/BF01712051

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