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Probing Self-Assembly of G Protein-Coupled Receptor Oligomers in Membranes Using Molecular Dynamics Modeling and Experimental Approaches

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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) transduce chemical signals across membranes and mediate many fundamental cellular signaling pathways. The “signalosome” is the basic signaling unit and comprises and an agonist ligand-receptor complex bound to a heterotrimeric guanine nucleotide-binding regulatory protein (G protein) in a biological membrane. Although in many cases, a monomeric GPCR is competent to transduce signals, the role of receptor dimerization and higher-order self-assembly and how receptor oligomers affect pharmacology and cellular physiology has emerged as one of the most intriguing and challenging problems in the field. Here we review recent insights gained from a multidisciplinary research approach using computational coarse grain molecular dynamics (CGMD) simulations and experiments facilitated by molecular and chemical biology approaches. One particular focus of recent work has been to define the contact sites between receptor dimers.

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Abbreviations

2-D:

two-dimensional

3-D:

three-dimensional

5-HT1AR:

serotonin1A receptor

A1AR:

adenosine A1A receptor

A2AR:

adenosine A2A receptor

AFM:

atomic force microscopy

β1-AR:

β1-adrenergic receptor

β2-AR:

β2-adrenergic receptor

BC:

benzylcytosine

BG:

benzylguanine

BRET:

bioluminescence resonance energy transfer

CGMD:

coarse-grain molecular dynamics

DAFT:

docking assay for TM components

DHA:

docosahexaenoic acid

DOPC:

1,2-dioleyl-sn-glycero-3-phosphocholine

DPPC:

1,2-dipalmitoyl-sn-glycero-3-phosphocholine

DSPC:

1,2-distearoyl-sn-glycero-3-phosphocholine

D2R:

dopamine D2 receptor

ECL:

extracellular loop

FCS:

fluorescence correlation spectroscopy

FPR:

N-formyl-peptide receptor

FRAP:

fluorescence recovery after photobleaching

G protein:

heterotrimeric guanine nucleotide-binding regulatory protein

GABA:

γ-aminobutyric acid

GFP:

green fluorescent protein

GPCRs:

G protein-coupled receptors

H:

helix

ICL:

intracellular loop

LHR:

luteinizing hormone receptor

mGlu1:

metabotropic glutamate receptor 1

meta-I:

metarhodopsin I

meta-II:

metarhodopsin-II

NSOM:

near-field scanning optical microscopy

OR:

opioid receptor

PIP:

phosphatidylinositol bisphosphate

PMF:

potential-of-mean-force

POPC:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

PUFA:

polyunsaturated fatty acid

ROS:

rod outer segment

RLuc:

Renilla luciferase

S1PR1 :

sphingosine 1-phosphate receptor 1

SDPC:

1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine

SDPE:

1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylethanolamine

SM:

sphingomyelin

SMLM:

single-molecule localization microscopy

SPT:

single-particle tracking

TM:

transmembrane

US:

umbrella sampling

WHAM:

weighted histogram analysis method

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Authors and Affiliations

  1. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden

    Thomas P. Sakmar M.D.

  2. Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Thomas P. Sakmar M.D. & Thomas Huber M.D., Ph.D.

  3. Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000, Aarhus C, Denmark

    Xavier Periole Ph.D.

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  1. Thomas P. Sakmar M.D.
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  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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Sakmar, T.P., Periole, X., Huber, T. (2017). Probing Self-Assembly of G Protein-Coupled Receptor Oligomers in Membranes Using Molecular Dynamics Modeling and Experimental Approaches. 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_15

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