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Originally published In Press as doi:10.1074/jbc.M006594200 on August 7, 2000

J. Biol. Chem., Vol. 275, Issue 43, 33633-33640, October 27, 2000
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Characterization of the Extra-large G Protein alpha -Subunit XLalpha s
II. SIGNAL TRANSDUCTION PROPERTIES*

Martin KlemkeDagger , H. Amalia PasolliDagger §, Ralph H. KehlenbachDagger , Stefan Offermanns||**, Günter Schultz||, and Wieland B. HuttnerDagger Dagger Dagger §§

From the Dagger  Department of Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Dagger Dagger  Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 110, D-01307 Dresden, and || Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Thielallee 67-73, D-14195 Berlin-Dahlem, Germany

In the preceding paper (Pasolli, H. A., Klemke, M., Kehlenbach, R. H., Wang, Y., and Huttner, W. B. (2000) J. Biol. Chem. 275, 33622-33632), we report on the tissue distribution and subcellular localization of XLalpha s (extra large alpha s), a neuroendocrine-specific, plasma membrane-associated protein consisting of a novel 37-kDa XL domain followed by a 41-kDa alpha s domain encoded by exons 2-13 of the Galpha s gene. Here, we have studied the signal transduction properties of XLalpha s. Like Galpha s, XLalpha s undergoes a conformational change upon binding of GTPgamma S (guanosine 5'-O-(thio)triphosphate), as revealed by its partial resistance to tryptic digestion, which generated the same fragments as in the case of Galpha s. Two approaches were used to analyze XLalpha s-beta gamma interactions: (i) ADP-ribosylation by cholera toxin to detect even weak or transient XLalpha s-beta gamma interactions and (ii) sucrose density gradient centrifugation to reveal stable heterotrimer formation. The addition of beta gamma subunits resulted in an increased ADP-ribosylation of XLalpha s as well as an increased sedimentation rate of XLalpha s in sucrose density gradients, indicating that XLalpha s interacts with the beta gamma dimer. Surprisingly, however, XLalpha s, in contrast to Galpha s, was not activated by the beta 2-adrenergic receptor upon reconstitution of S49cyc- membranes. Similarly, using photoaffinity labeling of pituitary membranes with azidoanilide-GTP, XLalpha s was not activated upon stimulation of pituitary adenylyl cyclase-activating polypeptide (PACAP) receptors or other Galpha s-coupled receptors known to be present in these membranes, whereas Galpha s was. Despite the apparent inability of XLalpha s to undergo receptor-mediated activation, XLalpha s-GTPgamma S markedly stimulated adenylyl cyclase in S49cyc- membranes. Moreover, transfection of PC12 cells with a GTPase-deficient mutant of XLalpha s, XLalpha s-Q548L, resulted in a massive increase in adenylyl cyclase activity. Our results suggest that in neuroendocrine cells, the two related G proteins, Galpha s and XLalpha s, exhibit distinct properties with regard to receptor-mediated activation but converge onto the same effector system, adenylyl cyclase.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF116268.

§ Recipient of a fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Present address: Centro de Microscopia Electronica, Universidad Nacional de Cordoba, C. Correo 362, 5000-Cordoba, Argentina.

Present address: Dept. of Virology, University of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.

** Present address: Dept. of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany.

§§ Supported by Deutsche Forschungsgemeinschaft Grants SPP GTPases, Hu 275/4-1, Hu 275/4-2; SFB 317, D2; SFB 352, C1, the German-Israeli Foundation for Scientific Research and Development, and the Fonds der Chemischen Industrie. To whom correspondence should be addressed. Tel.: 49-6221-548218; Fax: 49-6221-546700; E-mail: whuttner@sun0.urz.uni-heidelberg.de.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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