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Vol. 17, No. 1, 2009
Issue release date: February 2009
Free Access
Neurosignals 2009;17:100–108
(DOI:10.1159/000186693)

Heterotrimeric G-Proteins Interact Directly with Cytoskeletal Components to Modify Microtubule-Dependent Cellular Processes

Dave R.H.a · Saengsawang W.a · Yu J.-Z.a · Donati R.d · Rasenick M.M.a–c
Departments of aPhysiology and Biophysics and bPsychiatry, cGraduate Program in Neuroscience, University of Illinois Chicago, and dDepartment of Basic Sciences, Illinois College of Optometry, Chicago, Ill., USA
email Corresponding Author

Abstract

A large percentage of current drugs target G-protein-coupled receptors, which couple to well-known signaling pathways involving cAMP or calcium. G-proteins themselves may subserve a second messenger function. Here, we review the role of tubulin and microtubules in directly mediating effects of heterotrimeric G-proteins on neuronal outgrowth, shape and differentiation. G-protein-tubulin interactions appear to be regulated by neurotransmitter activity, and, in turn, regulate the location of Gα in membrane microdomains (such as lipid rafts) or the cytosol. Tubulin binds with nanomolar affinity to Gsα, Giα1 and Gqα (but not other Gα subunits) as well as Gβ1γ2 subunits. Gα subunits destabilize microtubules by stimulating tubulin’s GTPase, while Gβγ subunits promote microtubule stability. The same region on Gsα that binds adenylyl cyclase and Gβγ also interacts with tubulin, suggesting that cytoskeletal proteins are novel Gα effectors. Additionally, intracellular Giα-GDP, in concert with other GTPase proteins and Gβγ, regulates the position of the mitotic spindle in mitosis. Thus, G-protein activation modulates cell growth and differentiation by directly altering microtubule stability. Further studies are needed to fully establish a structural mechanism of this interaction and its role in synaptic plasticity.


 goto top of outline Key Words

  • G-protein
  • Tubulin
  • Lipid rafts
  • Microtubule-associated protein
  • Gs
  • Gβγ
  • Mitosis
  • Neurite outgrowth
  • GPCR
  • Synaptogenesis

 goto top of outline Abstract

A large percentage of current drugs target G-protein-coupled receptors, which couple to well-known signaling pathways involving cAMP or calcium. G-proteins themselves may subserve a second messenger function. Here, we review the role of tubulin and microtubules in directly mediating effects of heterotrimeric G-proteins on neuronal outgrowth, shape and differentiation. G-protein-tubulin interactions appear to be regulated by neurotransmitter activity, and, in turn, regulate the location of Gα in membrane microdomains (such as lipid rafts) or the cytosol. Tubulin binds with nanomolar affinity to Gsα, Giα1 and Gqα (but not other Gα subunits) as well as Gβ1γ2 subunits. Gα subunits destabilize microtubules by stimulating tubulin’s GTPase, while Gβγ subunits promote microtubule stability. The same region on Gsα that binds adenylyl cyclase and Gβγ also interacts with tubulin, suggesting that cytoskeletal proteins are novel Gα effectors. Additionally, intracellular Giα-GDP, in concert with other GTPase proteins and Gβγ, regulates the position of the mitotic spindle in mitosis. Thus, G-protein activation modulates cell growth and differentiation by directly altering microtubule stability. Further studies are needed to fully establish a structural mechanism of this interaction and its role in synaptic plasticity.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Adam RM, Yang W, Di Vizio D, Mukhopadhyay NK, Steen H: Rapid preparation of nuclei-depleted detergent-resistant membrane fractions suitable for proteomics analysis. BMC Cell Biol 2008;9:30.

    External Resources

  2. Allen JA, Halverson-Tamboli RA, Rasenick MM: Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 2007;8:128–140.
  3. Allen JA, Yu JZ, Donati RJ, Rasenick MM: β-Adrenergic receptor stimulation promotes Gαs internalization through lipid rafts: a study in living cells. Mol Pharmacol 2005;67:1493–1504.
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  7. Bünemann M, Frank M, Lohse MJ: Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 2003;100:16077–16082.

    External Resources

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 goto top of outline Author Contacts

Mark M. Rasenick
Departments of Physiology and Biophysics, Psychiatry, and
Graduate Program in Neuroscience, University of Illinois
Chicago, IL 60612-7342 (USA)
Tel. +1 312 996 6641, Fax +1 312 996 1414, E-Mail raz@uic.edu


 goto top of outline Article Information

Received: September 19, 2008
Accepted after revision: November 5, 2008
Published online: February 12, 2009
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 78


 goto top of outline Publication Details

Neurosignals

Vol. 17, No. 1, Year 2009 (Cover Date: February 2009)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

A large percentage of current drugs target G-protein-coupled receptors, which couple to well-known signaling pathways involving cAMP or calcium. G-proteins themselves may subserve a second messenger function. Here, we review the role of tubulin and microtubules in directly mediating effects of heterotrimeric G-proteins on neuronal outgrowth, shape and differentiation. G-protein-tubulin interactions appear to be regulated by neurotransmitter activity, and, in turn, regulate the location of Gα in membrane microdomains (such as lipid rafts) or the cytosol. Tubulin binds with nanomolar affinity to Gsα, Giα1 and Gqα (but not other Gα subunits) as well as Gβ1γ2 subunits. Gα subunits destabilize microtubules by stimulating tubulin’s GTPase, while Gβγ subunits promote microtubule stability. The same region on Gsα that binds adenylyl cyclase and Gβγ also interacts with tubulin, suggesting that cytoskeletal proteins are novel Gα effectors. Additionally, intracellular Giα-GDP, in concert with other GTPase proteins and Gβγ, regulates the position of the mitotic spindle in mitosis. Thus, G-protein activation modulates cell growth and differentiation by directly altering microtubule stability. Further studies are needed to fully establish a structural mechanism of this interaction and its role in synaptic plasticity.



 goto top of outline Author Contacts

Mark M. Rasenick
Departments of Physiology and Biophysics, Psychiatry, and
Graduate Program in Neuroscience, University of Illinois
Chicago, IL 60612-7342 (USA)
Tel. +1 312 996 6641, Fax +1 312 996 1414, E-Mail raz@uic.edu


 goto top of outline Article Information

Received: September 19, 2008
Accepted after revision: November 5, 2008
Published online: February 12, 2009
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 78


 goto top of outline Publication Details

Neurosignals

Vol. 17, No. 1, Year 2009 (Cover Date: February 2009)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Adam RM, Yang W, Di Vizio D, Mukhopadhyay NK, Steen H: Rapid preparation of nuclei-depleted detergent-resistant membrane fractions suitable for proteomics analysis. BMC Cell Biol 2008;9:30.

    External Resources

  2. Allen JA, Halverson-Tamboli RA, Rasenick MM: Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 2007;8:128–140.
  3. Allen JA, Yu JZ, Donati RJ, Rasenick MM: β-Adrenergic receptor stimulation promotes Gαs internalization through lipid rafts: a study in living cells. Mol Pharmacol 2005;67:1493–1504.
  4. Arthur DB, Akassoglou K, Insel PA: P2Y2 and TrkA receptors interact with Src family kinase for neuronal differentiation. Biochem Biophys Res Commun 2006;347:678–682.
  5. Arthur DB, Akassoglou K, Insel PA: P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proc Natl Acad Sci USA 2005;102:19138–19143.
  6. Arvanitis DN, Min W, Gong Y, Heng YM, Boggs JM: Two types of detergent-insoluble, glycosphingolipid/cholesterol-rich membrane domains from isolated myelin. J Neurochem 2005;94:1696–1710.
  7. Bünemann M, Frank M, Lohse MJ: Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 2003;100:16077–16082.

    External Resources

  8. Burnette DT, Schaefer AW, Ji L, Danuser G, Forscher P: Filopodial actin bundles are not necessary for microtubule advance into the peripheral domain of aplysia neuronal growth cones. Nat Cell Biol 2007;9:1360–1369.
  9. Calvert PD, Strissel KJ, Schiesser WE, Pugh EN Jr, Arshavsky VY: Light-driven translocation of signaling proteins in vertebrate photoreceptors. Trends Cell Biol 2006;16:560–568.
  10. Cazillis M, Gonzalez BJ, Billardon C, Lombet A, Fraichard A, Samarut J, Gressens P, Vaudry H, Rostène W: VIP and PACAP induce selective neuronal differentiation of mouse embryonic stem cells. Eur J Neurosci 2004;19:798–808.
  11. Chen NF, Yu JZ, Skiba NP, Hamm HE, Rasenick MM: A specific domain of Giα required for the transactivation of Giα by tubulin is implicated in the organization of cellular microtubules. J Biol Chem 2003;278:15285–15290.
  12. Ciruela F, Robbins MJ, Willis AC, McIlhinney RA: Interactions of the C-terminus of metabotropic glutamate receptor type 1α with rat brain proteins: evidence for a direct interaction with tubulin. J Neurochem 1999;72:346–354.
  13. David-Pfeuty T, Laporte J, Pantaloni D: GTPase activity at ends of microtubules. Nature 1978;272:282–284.
  14. David-Pfeuty T, Simon C, Pantaloni D: Effect of antimitotic drugs on tubulin GTPase activity and self-assembly. J Biol Chem 1979;254:11696–11702.
  15. Davis A, Sage CR, Dougherty CA, Farrell KW: Microtubule dynamics modulated by guanosine triphosphate hydrolysis activity of β-tubulin. Science 1994;264:839–842.
  16. Donati RJ, Rasenick MM: Chronic antidepressant treatment prevents accumulation of Gs in cholesterol-rich, cytoskeletal-associated plasma membrane domains (lipid rafts). Neuropsychopharmacology 2005;30:1238–1245.
  17. Fleury D, Grenningloh G, Lafanechene L, Antonsson B, Job D, Cohen-Addad C: Preliminary crystallographic study of a complex formed between the α/β-tubulin heterodimer and the neuronal growth-associated protein SCG10. J Struct Biol 2000;131:156–158.
  18. Foster LJ, de Hoog CL, Mann M: Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors. Proc Natl Acad Sci USA 2003;100:5813–5818.
  19. Gigant B, Wang C, Ravelli RB, Roussi F, Steinmetz MO, Curmi PA, Sobel A, Knossow M: Structural basis for the regulation of tubulin by vinblastine. Nature 2005;435:519–522.
  20. Gotta M, Ahringer J: Axis determination in C. elegans: initiating and transducing polarity. Curr Opin Genet Dev 2001;11:367–373.
  21. He JC, Neves SR, Jordan JD, Iyengar R: Role of the Go/i signaling network in the regulation of neurite outgrowth. Can J Physiol Pharmacol 2006;84:687–694.
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