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Review ArticleReview Article

Beyond the Ligand: Extracellular and Transcellular G Protein–Coupled Receptor Complexes in Physiology and Pharmacology

Henry A. Dunn, Cesare Orlandi and Kirill A. Martemyanov
Eric L. Barker, ASSOCIATE EDITOR
Pharmacological Reviews October 2019, 71 (4) 503-519; DOI: https://doi.org/10.1124/pr.119.018044
Henry A. Dunn
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida
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  • For correspondence: hdunn@scripps.edu
Cesare Orlandi
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida
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  • For correspondence: corlandi@scripps.edu
Kirill A. Martemyanov
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida
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  • For correspondence: kirill@scripps.edu
Eric L. Barker
Roles: ASSOCIATE EDITOR
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Abstract

G protein–coupled receptors (GPCRs) remain one of the most successful targets of U.S. Food and Drug Administration–approved drugs. GPCR research has predominantly focused on the characterization of the intracellular interactome’s contribution to GPCR function and pharmacology. However, emerging evidence uncovers a new dimension in the biology of GPCRs involving their extracellular and transcellular interactions that critically impact GPCR function and pharmacology. The seminal examples include a variety of adhesion GPCRs, such as ADGRLs/latrophilins, ADGRBs/brain angiogenesis inhibitors, ADGRG1/GPR56, ADGRG6/GPR126, ADGRE5/CD97, and ADGRC3/CELSR3. However, recent advances have indicated that class C GPCRs that contain large extracellular domains, including group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), γ-aminobutyric acid receptors, and orphans GPR158 and GPR179, can also participate in this form of transcellular regulation. In this review, we will focus on a variety of identified extracellular and transcellular GPCR-interacting partners, including teneurins, neurexins, integrins, fibronectin leucine-rich transmembranes, contactin-6, neuroligin, laminins, collagens, major prion protein, amyloid precursor protein, complement C1q-likes, stabilin-2, pikachurin, dystroglycan, complement decay-accelerating factor CD55, cluster of differentiation CD36 and CD90, extracellular leucine-rich repeat and fibronectin type III domain containing 1, and leucine-rich repeat, immunoglobulin-like domain and transmembrane domains. We provide an account on the diversity of extracellular and transcellular GPCR complexes and their contribution to key cellular and physiologic processes, including cell migration, axon guidance, cellular and synaptic adhesion, and synaptogenesis. Furthermore, we discuss models and mechanisms by which extracellular GPCR assemblies may regulate communication at cellular junctions.

SIGNIFICANCE STATEMENT G protein–coupled receptors (GPCRs) continue to be the prominent focus of pharmacological intervention for a variety of human pathologies. Although the majority of GPCR research has focused on the intracellular interactome, recent advancements have identified an extracellular dimension of GPCR modulation that alters accepted pharmacological principles of GPCRs. Herein, we describe known endogenous allosteric modulators acting on GPCRs both in cis and in trans.

Footnotes

  • Research in the Martemyanov laboratory in the area covered by this review is supported by the National Institutes of Health National Eye Institute [Grant R01 EY018139] and the National Institutes of Health National Institute of Mental Health [Grant R01 MH105482]. H.A.D. is the recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship.

  • https://doi.org/10.1124/pr.119.018044.

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 71 (4)
Pharmacological Reviews
Vol. 71, Issue 4
1 Oct 2019
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Review ArticleReview Article

Extracellular and Transcellular GPCR Complexes

Henry A. Dunn, Cesare Orlandi and Kirill A. Martemyanov
Pharmacological Reviews October 1, 2019, 71 (4) 503-519; DOI: https://doi.org/10.1124/pr.119.018044

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Review ArticleReview Article

Extracellular and Transcellular GPCR Complexes

Henry A. Dunn, Cesare Orlandi and Kirill A. Martemyanov
Pharmacological Reviews October 1, 2019, 71 (4) 503-519; DOI: https://doi.org/10.1124/pr.119.018044
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  • Article
    • Visual Overview
    • Abstract
    • I. The Emerging Extracellular Dimension of G Protein–Coupled Receptor Modulation
    • II. Group III Metabotropic Glutamate Receptors Are Classic Neurotransmitter Receptors Subject to Transsynaptic Control by Endogenous Allosteric Modulators
    • III. Alternative Splicing Defines the Extracellular Interactome of γ-Aminobutyric Acid Receptors
    • IV. Multimodal Assemblies Involving Adhesion G Protein–Coupled Receptor Subfamily Ls (Latrophilins) Modulate Axonal Attraction, Repulsion, and Synapse Formation
    • V. Direct Interaction of Adhesion G Protein–Coupled Receptor Subfamily G1/6 (G Protein–Coupled Receptor 56/126) with Extracellular Matrix Proteins Regulates Adhesion G Protein–Coupled Receptor Activation Mechanisms
    • VI. Bidirectional Transsynaptic Coordination of Signaling Involving Complexes Composed of Adhesion G Protein–Coupled Receptor B1-3 (Brain-Specific Angiogenesis Inhibitor 1-3)
    • VII. Assembly of Transsynaptic Complexes with Orphan G Protein–Coupled Receptor 158/179 Facilitates Bidirectional Scaffolding of Intracellular Signaling Molecules
    • VIII. Concluding Remarks
    • Acknowledgments
    • Authorship Contributions
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