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A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs

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Cholesterol Modulation of Protein Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1115))

Abstract

G protein-coupled receptors (GPCRs) are the largest and a diverse family of proteins involved in signal transduction across biological membranes. GPCRs mediate a wide range of physiological processes and have emerged as major targets for the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, regulation of their organization, dynamics, and function by membrane lipids, in particular membrane cholesterol, has emerged as an exciting area of research. Cholesterol sensitivity of GPCRs could be due to direct interaction of cholesterol with the receptor (specific effect). Alternately, GPCR function could be influenced by the effect of cholesterol on membrane physical properties (general effect). In this review, we critically analyze the specific and general mechanisms of the modulation of GPCR function by membrane cholesterol, taking examples from representative GPCRs. While evidence for both the proposed mechanisms exists, there appears to be no clear-cut distinction between these two mechanisms, and a combination of these mechanisms cannot be ruled out in many cases. We conclude that classifying the mechanism underlying cholesterol sensitivity of GPCR function merely into these two mutually exclusive classes could be somewhat arbitrary. A more holistic approach could be suitable for analyzing GPCR–cholesterol interaction.

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Abbreviations

7-DHC:

7-Dehydrocholesterol

7-DHCR:

3β-Hydroxy-steroid-Δ7-reductase

24-DHCR:

3β-Hydroxy-steroid-Δ24-reductase

AY 9944:

trans-1,4-bis(2-chlorobenzylaminoethyl)cyclohexane dihydrochloride

CB:

Cannabinoid receptor

CCK:

Cholecystokinin receptor

CCM:

Cholesterol consensus motif

CCR5:

CC chemokine receptor 5

CRAC:

Cholesterol recognition/interaction amino acid consensus

CXCR4:

CXC chemokine receptor 4

GalR2:

Galanin receptor 2

GPCR:

G protein-coupled receptor

MβCD:

Methyl-β-cyclodextrin

MI:

Metarhodopsin I

MII:

Metarhodopsin II

mGluR:

Metabotropic glutamate receptor

SLOS:

Smith–Lemli–Opitz syndrome

Smo:

Smoothened

T2R4:

Bitter taste receptor 4

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Acknowledgments

A.C. gratefully acknowledges support from SERB Distinguished Fellowship (Department of Science and Technology, Govt. of India). G.A.K. and B.D.R. thank the Council of Scientific and Industrial Research and University Grants Commission for the award of Senior Research Fellowships, respectively. A.C. is a Distinguished Visiting Professor at Indian Institute of Technology, Bombay (Mumbai), and Adjunct Professor at Tata Institute of Fundamental Research (Mumbai), RMIT University (Melbourne, Australia), and Indian Institute of Science Education and Research (Kolkata). Some of the work described in this article was carried out by former members of A.C.’s research group whose contributions are gratefully acknowledged. We thank members of the Chattopadhyay laboratory, particularly Parijat Sarkar, for comments and discussions.

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Authors and Affiliations

  1. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India

    Md. Jafurulla, G. Aditya Kumar & Amitabha Chattopadhyay

  2. CSIR-Indian Institute of Chemical Technology, Hyderabad, India

    Bhagyashree D. Rao

  3. Academy of Scientific and Innovative Research, Ghaziabad, India

    Bhagyashree D. Rao & Amitabha Chattopadhyay

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  1. Department of Chemistry, University of Illinois, Chicago, IL, USA

    Avia Rosenhouse-Dantsker

  2. The University of Tennessee Health Science Center, Memphis, TN, USA

    Anna N. Bukiya

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Jafurulla, M., Aditya Kumar, G., Rao, B.D., Chattopadhyay, A. (2019). A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs. In: Rosenhouse-Dantsker, A., Bukiya, A.N. (eds) Cholesterol Modulation of Protein Function. Advances in Experimental Medicine and Biology, vol 1115. Springer, Cham. https://doi.org/10.1007/978-3-030-04278-3_2

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