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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

Article Figures & Data

Figures

  • Figure1
  • Fig. 1.
    Fig. 1.

    Conventional GPCR signal transduction and the emergence of transcellular GPCR complexes. Traditionally, the extracellular surface of GPCRs is viewed as a site for interaction with ligands initiating GPCR-mediated intracellular signaling. This involves a conformational change and subsequent activation of the heterotrimeric G protein, thereby inducing the exchange of GDP for GTP on the Gα-subunit and the dissociation of Gα- from Gβγ-subunits. Subsequent Gα-mediated hydrolysis of GTP to GDP enables the reassociation with Gβγ to terminate G protein signaling, a process catalyzed by RGS proteins. However, it is now emerging that GPCRs also form a variety of extracellular interactions generalized in the scheme. These complexes are highly diversified and can create junction- or synapse-specific environments to endow GPCR function with specific properties.

  • Fig. 2.
    Fig. 2.

    The diversity and complexity of the GPCR extracellular interactome suggests functional and structural roles beyond traditional ligand activation. A multitude of proteins create direct or indirect links in cis and in trans with GPCR ectodomains. Proteins are represented schematically, and arrows represent validated protein–protein interactions of functional consequence.

Tables

  • TABLE 1

    Functional consequence of extracellular interactions with GPCRs

    Receptor (Alternate Name)PartnerStructureFunctional Consequences of Extracellular GPCR InteractionReference
    ADGRL1 (LPHN1)Contactin-6CisRole in neurite outgrowth and apoptosisZuko et al. (2016)
    ADGRL1 (LPHN1)Teneurin-2Trans/solubleSynaptogenic interaction. Purified teneurin-2 ectodomain induces Ca2+ release in presynaptic boutons of hippocampal neuronsSilva et al. (2011)
    ADGRL1 (LPHN1)Teneurin-2Trans/solubleRole in axonal attraction and fasciculation. Functional role in neuromuscular junction transmissionVysokov et al. (2018)
    ADGRL1 (LPHN1)Teneurin-2Trans/solubleInteraction in trans alters cAMP accumulation in ADGRL1-expressing cellsLi et al. (2018)
    ADGRL1-3 (LPHN1-3)Teneurin-2, teneurin-4Trans/solubleInduces cellular aggregation and junction formation. Interruption of interaction decreases synaptic density in cultured neuronsBoucard et al. (2014)
    ADGRL1-3 (LPHN1-3)FLRT3TransInterruption of interaction decreases synaptic density in cultured neuronsBoucard et al. (2014)
    ADGRL1 (LPHN1)FLRT3TransRole in defining excitatory synapse density, afferent input strength, and dendritic spine numberO’Sullivan et al. (2012)
    ADGRL3 (LPHN3)FLRT2TransInteraction facilitates adhesion in HeLa cells and repulsion in cortical neuronsJackson et al. (2015)
    ADGRL1 (LPHN1)FLRT2TransComplex with Unc5D inhibits cell adhesionJackson et al. (2016)
    ADGRL1 (LPHN1)NRXN1TransADGRL1 competes with neuroligin to form a transcellular adhesion complex with neurexinBoucard et al. (2012)
    ADGRC3 (CELSR3)DystroglycanTransRole in axon guidanceLindenmaier et al. (2019)
    ADGRB3 (BAI3)C1ql3SolubleCa2+-dependent interaction with TSRs in ADGRB3 ectodomainBolliger et al. (2011)
    ADGRB3 (BAI3)C1ql1SolubleRole in motor learning at climbing fiber-Purkinje cell synapsesKakegawa et al. (2015)
    ADGRB3 (BAI3)C1ql1SolubleC1ql1’s modulation of Purkinje cell spinogenesis is ADGRB3 dependentSigoillot et al. (2015)
    ADGRB3 (BAI3)C1ql4SolubleC1ql4 interacts with ADGRB3 to suppress myoblast fusionHamoud et al. (2014)
    ADGRB3 (BAI3)Stabilin-2CisStabilin-2 interacts in cis to promote G protein activation via ADGRB3 and activate myoblast fusionHamoud et al. (2014)
    ADGRB1 (BAI1)Neuroligin-1CisRole in spinogenesis, excitatory synaptogenesis, and presynaptic clustering of vGlut1 with neuroligin-neurexin transcomplexTu et al. (2018)
    ADGRB1 (BAI1)Integrin αVβ5TransADGRB1 ectodomain shows antiproliferative effects by blocking αVβ5 integrinKoh et al. (2004)
    ADGRB1 (BAI1)CD36TransADGRB1 released ectodomain mediates antivascular effects by interacting with CD36Kaur et al. (2009)
    ADGRE5 (CD97)CD55TransRole in cell adhesionHamann et al. (1996)
    ADGRE5 (CD97)CD55TransPromotes receptor desensitization after ectodomain cleavageKarpus et al. (2013)
    ADGRE5 (CD97)CD90TransRole in leukocyte adhesion to activated endothelium during inflammatory processesWandel et al. (2012)
    ADGRE5 (CD97)Integrin α5β1TransInteraction initiates endothelial cell invasion by inflammatory cellsWang et al. (2005)
    ADGRG1 (GPR56)Collagen IIISolublePromotes ADGRG1-dependent calcium signaling in pancreatic islet β cellsOlaniru et al. (2018)
    ADGRG1 (GPR56)Collagen IIISolubleInteraction activates Gα12/13-RhoA to control neuronal progenitor migration and corticogenesisLuo et al. (2011, 2014)
    ADGRG6 (GPR126)Collagen IVSolubleCollagen IV treatment of ADGRG6-expressing cells increases cAMPPaavola et al. (2014)
    ADGRG6 (GPR126)Laminin-211SolubleLaminin-211 promotes myelination through ADGRG6 in vivo. Interaction reduces cAMP via ADGRG6Petersen et al. (2015)
    ADGRG6 (GPR126)PrPSolublePrP activates ADGRG6 to increase cAMPKüffer et al. (2016)
    GPR179PikachurinSolublePikachurin recruits GPR179-RGS complex to photoreceptor postsynaptic sitesOrlandi et al. (2018)
    GPR158Glypican4TransRole in presynaptic differentiation and defining input-specific synaptic properties at mossy fiber-CA3 synapses in hippocampusCondomitti et al. (2018)
    mGluR7ELFN1TransSoluble ectodomain promotes constitutive activityStachniak et al. (2019)
    mGluR7ELFN1TransRole in synaptic targeting of mGluR7Tomioka et al. (2014)
    mGluR6ELFN1TransRole in promoting mGluR6 expression and synaptic targetingCao et al. (2015)
    mGluR4/6ELFN1TransAllosteric modulation of mGluR4/6 via G protein coupling mechanisms. Promotes constitutive activityDunn et al. (2018)
    GABABR1aAPP/sAPPSolubleModulates GABABR1a axonal trafficking and signaling to decrease vesicle release probabilityDinamarca et al. (2019), Rice et al. (2019)

    • BAI, brain-specific angiogenesis inhibitor; LPHN, latrophilin; TSR, thrombospondin repeat.

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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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