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Interaction of Membrane Cholesterol with GPCRs: Implications in Receptor Oligomerization

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G-Protein-Coupled Receptor Dimers

Part of the book series: The Receptors ((REC,volume 33))

Abstract

G protein-coupled receptors (GPCRs) are the largest family of proteins involved in signal transduction across cell membranes, and represent major drug targets in all clinical areas. Oligomerization of GPCRs and its implications in drug discovery constitute an exciting area in contemporary biology. In this review, we have highlighted the role of membrane cholesterol and the actin cytoskeleton in GPCR oligomerization, using a combined approach of homo-FRET and coarse-grain molecular dynamics simulations. In the process, we have highlighted experimental and computational methods that have been successful in analyzing different facets of GPCR association. Analysis of photobleaching homo-FRET data provided novel information about the presence of receptor oligomers under varying conditions. Molecular dynamics simulations have helped to pinpoint transmembrane helices that are involved in forming the receptor dimer interface, and this appears to be dependent on membrane cholesterol content. This gives rise to the exciting and challenging possibility of age and tissue dependence of drug efficacy. We envision that GPCR oligomerization could be a game changer in future drug discovery.

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Acknowledgments

D.S. and A.C. gratefully acknowledge the support of Ramalingaswami Fellowship from the Department of Biotechnology, and J.C. Bose Fellowship from the Department of Science and Technology, Govt. of India, respectively. G.A.K. thanks the Council of Scientific and Industrial Research (Govt. of India) for the award of a Senior Research Fellowship. A.C. is an Adjunct Professor of Tata Institute of Fundamental Research (Mumbai), RMIT University (Melbourne, Australia), Indian Institute of Technology (Kanpur), and Indian Institute of Science Education and Research (Mohali). We thank members of the Chattopadhyay laboratory for their comments and discussions, and Xavier Prasanna for help with the figures.

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Authors and Affiliations

  1. CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India

    Durba Sengupta

  2. CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India

    G. Aditya Kumar & Amitabha Chattopadhyay

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  1. Durba Sengupta
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  2. G. Aditya Kumar
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  3. Amitabha Chattopadhyay
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Correspondence to Durba Sengupta or Amitabha Chattopadhyay .

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Editors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA

    Katharine Herrick-Davis

  2. Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

    Graeme Milligan

  3. Department of Physiology and Biochemistry, University of Malta, Msida, Malta

    Giuseppe Di Giovanni

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Sengupta, D., Kumar, G.A., Chattopadhyay, A. (2017). Interaction of Membrane Cholesterol with GPCRs: Implications in Receptor Oligomerization. In: Herrick-Davis, K., Milligan, G., Di Giovanni, G. (eds) G-Protein-Coupled Receptor Dimers. The Receptors, vol 33. Humana Press, Cham. https://doi.org/10.1007/978-3-319-60174-8_16

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