Functional significance of serotonin receptor dimerization

Herrick‐Davis, Katharine

doi:10.1007/s00221-013-3622-1

Cited by 53 publications

(36 citation statements)

References 106 publications

(222 reference statements)

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“…These novel characteristics will help develop more selective drugs that have fewer side effects. Recent studies demonstrate that monovalent drugs specific for GPCR heterodimers43 and bivalent ligands4445 are powerful tools for evaluating activation of signaling pathways and cellular responses elicited by GPCR dimerization and oligomerization. Further studies are needed to generate specific agonists for APJ dimers/oligomers to investigate the novel G-protein binding characteristic of APJ dimers.…”

Section: Discussionmentioning

confidence: 99%

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Cai

Bai

Zhang

et al. 2017

Sci Rep

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The apelin receptor (APJ) belongs to family A of the G protein-coupled receptors (GPCRs) and is a potential pharmacotherapeutic target for heart failure, hypertension, and other cardiovascular diseases. There is evidence APJ heterodimerizes with other GPCRs; however, the existence of APJ homodimers and oligomers remains to be investigated. Here, we measured APJ monomer-homodimer-oligomer interconversion by monitoring APJ dynamically on cells and compared their proportions, spatial arrangement, and mobility using total internal reflection fluorescence microscopy, resonance energy transfer, and proximity biotinylation. In cells with <0.3 receptor particles/μm2, approximately 60% of APJ molecules were present as dimers or oligomers. APJ dimers were present on the cell surface in a dynamic equilibrium with constant formation and dissociation of receptor complexes. Furthermore, we applied interference peptides and MALDI-TOF mass spectrometry to confirm APJ homo-dimer and explore the dimer-interfaces. Peptides corresponding to transmembrane domain (TMD)1, 2, 3, and 4, but not TMD5, 6, and 7, disrupted APJ dimerization. APJ mutants in TMD1 and TMD2 also decreased bioluminescence resonance energy transfer of APJ dimer. APJ dimerization resulted in novel functional characteristics, such as a distinct G-protein binding profile and cell responses after agonist stimulation. Thus, dimerization may serve as a unique mechanism for fine-tuning APJ-mediated functions.

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Section: Discussionmentioning

confidence: 99%

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Cai

Bai

Zhang

et al. 2017

Sci Rep

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“…Although many studies report the identification of homodimers and higher-order oligomers of GPCR expressed in recombinant cell systems (reviewed in Herrick-Davis, 2013;Milligan, 2013;Ferré et al, 2014), few studies have examined the properties of native GPCRs. This is due to the technical challenges associated with developing selective probes for labeling native receptors along with sensitive methods capable of directly monitoring native protein-protein interactions in living cells.…”

Section: Discussionmentioning

confidence: 99%

“…Dimer/oligomer formation has been reported to regulate all aspects of GPCR function including synthesis, ligand binding, G protein coupling, and trafficking (reviewed in Herrick-Davis, 2013;Milligan, 2013). Even so, the presence and functional relevance of GPCR dimerization in vivo is widely debated (reviewed in Ferré et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Native Serotonin 5-HT_2CReceptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells

et al. 2015

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G protein-coupled receptors (GPCRs) are a prominent class of plasma membrane proteins that regulate physiologic responses to a wide variety of stimuli and therapeutic agents. Although GPCR oligomerization has been studied extensively in recombinant cells, it remains uncertain whether native receptors expressed in their natural cellular environment are monomers, dimers, or oligomers. The goal of this study was to determine the monomer/oligomer status of a native GPCR endogenously expressed in its natural cellular environment. Native 5-HT 2C receptors in choroid plexus epithelial cells were evaluated using fluorescence correlation spectroscopy (FCS) with photon counting histogram (PCH). An anti-5-HT 2C fragment antigen binding protein was used to label native 5-HT 2C receptors. A known monomeric receptor (CD-86) served as a control for decoding the oligomer status of native 5-HT 2C receptors by molecular brightness analysis. FCS with PCH revealed molecular brightness values for native 5-HT 2C receptors equivalent to the molecular brightness of a homodimer. 5-HT 2C receptors displayed a diffusion coefficient of 5 Â 10 29 cm 2 /s and were expressed at 32 receptors/mm 2 on the apical surface of choroid plexus epithelial cells. The functional significance and signaling capabilities of the homodimer were investigated in human embryonic kidney 293 cells using agonists that bind in a washresistant manner to one or both protomers of the homodimer. Whereas agonist binding to one protomer resulted in G protein activation, maximal stimulation required occupancy of both protomers. This study is the first to demonstrate the homodimeric structure of 5-HT 2C receptors endogenously expressed in their native cellular environment, and identifies the homodimer as a functional signaling unit.

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“…38 In fact, 5-HT imbalances are oen correlated with psychological disorders such as insomnia, anxiety, depression, and psychosis. [40][41][42] Interestingly, 5-HT receptors also form homodimers or heterodimers among themselves or other Gprotein-coupled receptors (GPCRs), respectively, which greatly enhances the complexity of their functions. 43 pCPA is an inhibitor of 5-HT synthesis.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxybenzyl alcohol derivatives and their sedative–hypnotic activities

Zhu

Zhang

Zhang³

et al. 2018

RSC Adv.

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a 4-Hydroxybenzyl alcohol (HBA), one of the characteristic active components of Gastrodia elata, exhibits obvious effects on the human central nervous system. In order to acquire compounds with superior bioactivity, 10 derivatives of HBA were synthesized from HBA and carboxylic acids. The sedative effects of the 10 HBA derivatives were evaluated using a spontaneous locomotor activity test (SLT) in mice, and their hypnotic effects were determined to be synergistic with pentobarbital-induced sleep. The results showed that 4-hydroxybenzyl alcohol 3-furancarboxylic acid diester (2FHBA, 10 mg kg À1 ) exhibited the strongest sedative-hypnotic activity among HBA and its derivatives, and 2FHBA could reverse the insomnia caused by p-chlorophenylalanine (pCPA), flumazenil (FLU) and thiosemicarbazide (TSC). Meanwhile, 2FHBA and 5-hydroxytryptophan (5-HTP) showed a synergistic effect. The results suggested that 2FHBA might be a potential agent against insomnia, which might be mediated by the serotonergic and GABAergic systems.

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Functional significance of serotonin receptor dimerization

Cited by 53 publications

References 106 publications

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Native Serotonin 5-HT_2CReceptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells

4-Hydroxybenzyl alcohol derivatives and their sedative–hypnotic activities

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Functional significance of serotonin receptor dimerization

Cited by 53 publications

References 106 publications

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

Native Serotonin 5-HT2CReceptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells

4-Hydroxybenzyl alcohol derivatives and their sedative–hypnotic activities

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Native Serotonin 5-HT_2CReceptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells