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

  • Md. Jafurulla
  • G. Aditya Kumar
  • Bhagyashree D. Rao
  • Amitabha ChattopadhyayEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

GPCR–cholesterol interaction Specific effect General effect Cholesterol binding motifs 

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

Notes

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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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Md. Jafurulla
    • 1
  • G. Aditya Kumar
    • 1
  • Bhagyashree D. Rao
    • 2
    • 3
  • Amitabha Chattopadhyay
    • 1
    • 3
    Email author
  1. 1.CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia
  2. 2.CSIR-Indian Institute of Chemical TechnologyHyderabadIndia
  3. 3.Academy of Scientific and Innovative ResearchGhaziabadIndia

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