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

Dunn, Henry A.; Orlandi, Cesare; Martemyanov, Kirill A.

doi:10.1124/pr.119.018044

Cited by 51 publications

(35 citation statements)

References 170 publications

(277 reference statements)

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“…At the same time GPR179 acts as a scaffold for many components of the post-synaptic mGluR6-G o -TRPM1 signaling complex (Orlandi, Cao, & Martemyanov, 2013). Moreover, their long extracellular N-termini have been shown to interact with extracellular matrix components to form trans-synaptic complexes (Condomitti et al, 2018; Dunn, Orlandi, & Martemyanov, 2019; Orlandi et al, 2018). Our results here indicate that GPR158 and GPR179 can simultaneously activate G proteins of the G i/o family while scaffolding R7-RGS proteins, which act as GTPase activating proteins (GAP) for a subset of Gα i/o family members to terminate the G protein signal.…”

Section: Discussionmentioning

confidence: 99%

In vitroprofiling of orphan G protein coupled receptor (GPCR) constitutive activity

Watkins

Orlandi

2021

Preprint

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Background and Purpose Members of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets. Experimental Approach The majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13 protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs. Key Results Using this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes. Conclusion and Implications We provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.

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Section: Discussionmentioning

confidence: 99%

In vitroprofiling of orphan G protein coupled receptor (GPCR) constitutive activity

Watkins

Orlandi

2021

Preprint

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“…It has been suggested that group III mGluRs act as auto-receptors during repetitive stimulations and modulate release probability (Billups et al , 2005; Pinheiro & Mulle, 2008). On the other hand, it has been described that mGluR7 is constitutively active (Kammermeier, 2015; Dunn et al , 2018; Stachniak et al , 2019), and that activity of group III mGluRs is regulated by the transsynaptic interaction with ELFN1/2 at excitatory synapses (Dunn et al , 2019a; Stachniak et al , 2019). Allosteric modulation of mGluR7 by ELFN1/2 could thus alter the threshold for receptor activation or increase its basal activity.…”

Section: Discussionmentioning

confidence: 99%

Subsynaptic mobility of presynaptic mGluR types is differentially regulated by intra- and extracellular interactions

Bodzęta

Berger

MacGillavry

2020

Preprint

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ABSTRACTPresynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.

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“…For example, some of the GPCRs in the adhesion group (class B) are extracellularly bound by single-transmembrane receptors [in-trans: teneurin 1–4, neurexin 1–3, fibronectin leucine-rich transmembrane 1–3 (Flrt1–Flrt3); in cis: contactin 6, stabilin 2, and neuroligin] and extracellular matrix proteins (Knapp and Wolfrum, 2016 ; Dunn et al, 2019a ). The extracellular interactions of GPCRs in the adhesion group are involved in synaptogenesis, neurite outgrowth, and axon guidance.…”

Section: Introductionmentioning

confidence: 99%

“…However, interestingly, the trans-interaction of the two classes of GPCR–LRRFn plays a role in closely related neural circuits ( Figures 1C–G ). Since there have been detailed reviews about Lphn3– or Lphn3–Flrt3 interaction ( Figure 1G ; Ranaivoson et al, 2015 ; Knapp and Wolfrum, 2016 ; Dunn et al, 2019a ; Bruxel et al, 2020 ), this article is focused on the Elfn–mGluR interaction and its relevance to Flrt–Lphn trans-interaction.…”

Section: Introductionmentioning

confidence: 99%

Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

Matsunaga

Aruga

2021

Front. Neural Circuits

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Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR–GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR–GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn–mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1–mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1–mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.

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

Cited by 51 publications

References 170 publications

In vitroprofiling of orphan G protein coupled receptor (GPCR) constitutive activity

In vitroprofiling of orphan G protein coupled receptor (GPCR) constitutive activity

Subsynaptic mobility of presynaptic mGluR types is differentially regulated by intra- and extracellular interactions

Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

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