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RGS8 accelerates G-protein-mediated modulation of K+currents

Nature volume 390, pages 525–529 (1997)Cite this article

Abstract

Transmembrane signal transduction via heterotrimeric G proteins is reported to be inhibited by RGS (regulators of G-protein signalling) proteins1,2,3,4. These RGS proteins work by increasing the GTPase activity of G protein α-subunits (Gα), thereby driving G proteins into their inactive GDP-bound form5,6,7. However, it is not known how RGS proteins regulate the kinetics of physiological responses that depend on G proteins. Here we report the isolation of a full-length complementary DNA encoding a neural-tissue-specific RGS protein, RGS8, and the determination of its function. We show that RGS8 binds preferentially to the α-subunits Gαo and Gαi3 and that it functions as a GTPase-activating protein (GAP). When co-expressed in Xenopus oocytes with a G-protein-coupled receptor and a G-protein-coupled inwardly rectifying K+channel (GIRK1/2), RGS8 accelerated not only the turning off but also the turning on of the GIRK1/2 current upon receptor stimulation, without affecting the dose–response relationship. We conclude that RGS8 accelerates the modulation of G-protein-coupled channels and is not just a simple negative regulator. This property of RGS8 may be crucial for the rapid regulation of neuronal excitability upon stimulation of G-protein-coupled receptors.

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Figure 1: Detection and characterization of RGS8.
Figure 2: Interaction of RGS8 with Gα subunit.
Figure 3: Effects of RGS8 on GTP hydrolysis of Gαo.
Figure 4: Effects of RGS8 on turning-on and turning-off kinetics, and on the dose–response relationships of the G-protein-coupled inwardly rectifying K+channel (GIRK1/2) current upon stimulation of the receptors.

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Acknowledgements

We thank M. Lazdunski for GIRK2 cDNA, A. Connolly for m2 muscarinic receptor and D2 dopamine receptor cDNA, K. Yamagata for the cDNA library, M. Odagiri for technical assistance. This work is supported by research grants from the Ministry of Education, Science, Sports and Culture of Japan (to O.S.) and from the Human Frontier Science Program Organization (to Y.K.) and by a grant-in-aid for scientific research on priority area of “channel-Transporter Correlation” (to Y.K.).

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Authors and Affiliations

  1. Department of Molecular,

    Osamu Saitoh, Yoshihide Miyatani & Hiroyasu Nakata

  2. Cellular Neurobiology,

    Osamu Saitoh, Yoshihide Miyatani & Hiroyasu Nakata

  3. Department of Neurophysiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo, 183, Japan

    Yoshihiro Kubo

  4. Department of Biochemistry, Institute for Developmental Research, Aichi Human Service Center, Kasugai, 480-03, Aichi, Japan

    Tomiko Asano

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  1. Osamu Saitoh
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Correspondence to Osamu Saitoh or Hiroyasu Nakata.

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Saitoh, O., Kubo, Y., Miyatani, Y. et al. RGS8 accelerates G-protein-mediated modulation of K+currents. Nature 390, 525–529 (1997). https://doi.org/10.1038/37385

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