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Papers In Press, published online ahead of print August 7, 2000
Neurobiology, University of Heidelberg, Heidelberg D-69120
Corresponding Author: whuttner{at}sun0.urz.uni-heidelberg.de
In the preceding paper (Pasolli et al.), we report on the tissue distribution and subcellular localization of XLas ("extra-large" as), a neuroendocrine-specific, plasma membrane-associated protein consisting of a novel 37 kDa XL-domain followed by a 41 kDa as-domain encoded by exons 2-13 of the Gas gene. Here, we have studied the signal transduction properties of XLas. Like Gas, XLas undergoes a conformational change upon binding of guanosine 5´-O-(thio)triphosphate (GTPgS), as revealed by its partial resistance to tryptic digestion, which generated the same fragments as in the case of Gas. Two approaches were used to analyze XLas?bg interactions, (i) ADP-ribosylation by cholera toxin to detect even weak or transient XLas?bg interactions, and (ii) sucrose density gradient centrifugation to reveal stable heterotrimer formation. Addition of bg subunits resulted in an increased ADP-ribosylation of XLas as well as an increased sedimentation rate of XLas in sucrose density gradients, indicating that XLas interacts with the bg dimer. Surprisingly, however, XLas, in contrast to Gas, was not activated by the b2-adrenergic receptor upon reconstitution of S49cyc? membranes. Similarly, using photoaffinity labeling of pituitary membranes with azidoanilido-GTP, XLas was not activated upon stimulation of PACAP receptors or other Gas-coupled receptors known to be present in these membranes, whereas Gas was. Despite the apparent inability of XLas to undergo receptor-mediated activiation, XLas?GTPgS markedly stimulated adenylyl cyclase in S49cyc? membranes. Moreover, transfection of PC12 cells with a GTPase-deficient mutant of XLas, XLas-Q548L, resulted in a massive increase in adenylyl cyclase activity. Our results suggest that in neuroendocrine cells, the two related G proteins Gas and XLas exhibit distinct properties with regard to receptor-mediated activation but converge onto the same effector system, adenylyl cyclase.
J. Biol. Chem, 10.1074/jbc.M006594200
Submitted on July 24, 2000
Revised on August 6, 2000
Accepted on August 7, 2000
Characterization of the extra-large G-protein
-subunit XLs. II. Signal transduction properties
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