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Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization

Nature Cell Biology volume 2, pages 507–514 (2000)Cite this article

Abstract

Phosphatidylinositol bisphosphate (PIP2) directly regulates functions as diverse as the organization of the cytoskeleton, vesicular transport and ion channel activity. It is not known, however, whether dynamic changes in PIP2 levels have a regulatory role of physiological importance in such functions. Here, we show in both native cardiac cells and heterologous expression systems that receptor-regulated PIP2 hydrolysis results in desensitization of a GTP-binding protein-stimulated potassium current. Two receptor-regulated pathways in the plasma membrane cross-talk at the level of these channels to modulate potassium currents. One pathway signals through the βγ subunits of G proteins, which bind directly to the channel. Gβγ subunits stabilize interactions with PIP2 and lead to persistent channel activation. The second pathway activates phospholipase C (PLC) which hydrolyses PIP2 and limits Gβγ-stimulated activity. Our results provide evidence that PIP2 itself is a receptor-regulated second messenger, downregulation of which accounts for a new form of desensitization.

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Figure 1: Blocking receptor, Gqα or PLC attenuates K+ current desensitization in rat atrial myocytes.
Figure 2: PLC activation via M1 receptor stimulation in COS-1 cells results in rapidly desensitizing GIRK currents.
Figure 3: PLC activation via M1 receptor stimulation in COS-1 cells results in PIP2 hydrolysis.
Figure 4: M1 receptor signalling causes inhibition of GIRK currents in Xenopus laevis oocytes.
Figure 5: Hydrolysis of PIP2 through EGF receptor signalling causes inhibition of M2-stimulated GIRK currents in Xenopus oocytes.
Figure 6: An increase in the strength of GIRK4* channel- PIP2 interactions reduces agonist-induced current inhibition in Xenopus oocytes.
Figure 7: A decrease in the strength of IRK1 channel-PIP2 interactions confers agonist-induced current inhibition in Xenopus oocytes.

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Acknowledgements

We are grateful to X. Yan for preparation of oocytes, S. Henderson for help with the confocal experiments, and I. Wolf for peptide synthesis. We thank H. S. Wiley (University of Utah), X-Y. Huang (Cornell University Medical College) and T. Meyer (Duke University) for their kind gifts of EGF receptor, M1 receptor and GFP–PH cDNAs, respectively. We also thank R. Anderson, D. Clapham, M. Greenberg, R. Iyengar, R. Margolskee, S. Sealfon, M. Ming Zhou and members of the Logothetis lab for critical comments on the manuscript. This work was supported by grants to D.E.L. from the NIH (HL54185 and HL59949). T.M. was supported by NIH Training Grant DK 07757 and a Charles H. Revson fellowship.

Correspondence and requests for materials should be addressed to D.E.L.

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Authors and Affiliations

  1. Departments of Physiology & Biophysics,

    Evgeny Kobrinsky, Hailin Zhang, Taihao Jin & Diomedes E. Logothetis

  2. Medicine, Mount Sinai School of Medicine of the New York University, New York, New York, 10029, USA

    Tooraj Mirshahi

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Correspondence to Diomedes E. Logothetis.

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Kobrinsky, E., Mirshahi, T., Zhang, H. et al. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization . Nat Cell Biol 2, 507–514 (2000). https://doi.org/10.1038/35019544

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