Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context

Bailey, Sian; Harris, Matthew; Barkan, Kerry; Winfield, Ian J.; Harper, Matthew T.; Simms, John; Ladds, Graham; Wheatley, Mark; Poyner, David R.

doi:10.1016/j.bbamem.2019.02.008

Cited by 17 publications

(21 citation statements)

References 21 publications

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“…CRHR2 showed a very low probability of complex formation with RAMP3, but not with RAMP1 and RAMP2. These receptors had been judged not to form complexes with RAMPs because overexpression of the receptors in HEK293 or COS-7 cells did not cause coexpressed RAMPs to translocate to the cell surface (9,12). Our results directly show the existence of GPCR-RAMP complexes and suggest that RAMP translocation studies may not be sensitive to detect all GPCR-RAMP interactions (24).…”

Section: Discussionmentioning

confidence: 80%

“…Interaction of RAMPs with GPCRs has since been demonstrated with several additional members of the secretin-like GPCRs. RAMPs can influence several features of GPCR biology, including trafficking to the cell membrane, ligand specificity, downstream signaling, and recycling (4)(5)(6)(7)(8)(9)(10)(11)(12). However, many of the secretin-like GPCR-RAMP interactions remain unverified, and most of the interactions have not been demonstrated using a direct binding assay.…”

Section: Introductionmentioning

confidence: 99%

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Multiplexed analysis of the secretin-like GPCR-RAMP interactome

et al. 2019

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Receptor activity–modifying proteins (RAMPs) have been shown to modulate the functions of several G protein–coupled receptors (GPCRs), but potential direct interactions among the three known RAMPs and hundreds of GPCRs have never been investigated. Focusing mainly on the secretin-like family of GPCRs, we engineered epitope-tagged GPCRs and RAMPs, and developed a multiplexed suspension bead array (SBA) immunoassay to detect GPCR-RAMP complexes from detergent-solubilized lysates. Using 64 antibodies raised against the native proteins and 4 antibodies targeting the epitope tags, we mapped the interactions among 23 GPCRs and 3 RAMPs. We validated nearly all previously reported secretin-like GPCR-RAMP interactions, and also found previously unidentified RAMP interactions with additional secretin-like GPCRs, chemokine receptors, and orphan receptors. The results provide a complete interactome of secretin-like GPCRs with RAMPs. The SBA strategy will be useful to search for additional GPCR-RAMP complexes and other interacting membrane protein pairs in cell lines and tissues.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Multiplexed analysis of the secretin-like GPCR-RAMP interactome

et al. 2019

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“…Subsequent studies have further defined critical roles for RAMPs to impart biased downstream signaling and intracellular trafficking dynamics to numerous GPCRs. However, these pleiotropic effects of RAMPs have mostly been studied in the context of a few receptors in the Family B/Secretin family, including the calcitonin receptor (CTR), secretin receptor, glucagon (6, 7), CRF 1 (8,9), and VPAC 1/2 (8) and the Family A receptors CaSR (10) and GPR30/GPER1 (11). The strong coevolution of RAMPs with most GPCR families suggests that they may have expanded interacting partners (12,13).…”

mentioning

confidence: 99%

RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis

Mackie

Nielsen

Harris

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-activity–modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein–coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.

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“…Hornigold, Jacqueline Naylor and Alessandra Rossi (MedImmune, Cambridge, UK), and used as described elsewhere (38). ∆CTR-HEK 293 cells were cultured in MEM supplemented with 10% heat-inactivated FBS plus 1% non-essential amino acids.…”

Section: Receptor Binding Studies Cell Culture and Transient Transfementioning

confidence: 99%

GLP-1(9-36) mediates the glucagonostatic effect of GLP-1 by promiscuous activation of the glucagon receptor

Guida

Miranda

et al. 2019

Preprint

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Plasma glucose is controlled by the hormones glucagon and insulin. In type 2 diabetes, where insulin secretion is too low and glucagon secretion too high, elevated plasma glucose levels occur. Therefore, optimal therapeutic interventions aim to both enhance insulin secretion and inhibit glucagon release. The incretin hormone glucagon-like peptide 1 (GLP-1) possesses this capacity but the underlying mechanisms by which it suppresses glucagon release are unclear as glucagon-secreting α-cells express the receptor for GLP-1 at very low levels. Nevertheless, GLP-1 inhibit glucagon secretion by a direct (intrinsic) action in α-cells. Here, we examined the underlying mechanisms. We found that GLP-1 inhibits glucagon secretion at concentrations as low as 1-10 pM in isolated mouse and human islets. The degradation product GLP-1(9-36) inhibited glucagon secretion with similar potency. Whereas the effect of GLP-1 was sensitive to the PKA inhibitor 8-Br-Rp-cAMPS, GLP-1(9-36) exerted its effect by a PKA-independent mechanism that was sensitive to pretreatment with pertussis toxin (implicating an inhibitory GTP-binding protein). The glucagonostatic effect of GLP-1 was retained in islets from Glp1r knockout mice.Receptor signaling studies suggest that GLP-1(9-36) may activate glucagon receptors (GCGRs) and GCGR antagonism prevented the inhibitory effects of GLP-1(9-36). In vivo, GLP-1(9-36) reduced counter-regulatory glucagon secretion and enhanced the plasma glucose-lowering effect of exogenous insulin in mice fasted for 5-18h. We propose that GLP-1(7-36) and GLP-1(9-36) regulate glucagon secretion via interaction with both GLP-1R and GCGR.

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Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context

Cited by 17 publications

References 21 publications

Multiplexed analysis of the secretin-like GPCR-RAMP interactome

Multiplexed analysis of the secretin-like GPCR-RAMP interactome

RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis

GLP-1(9-36) mediates the glucagonostatic effect of GLP-1 by promiscuous activation of the glucagon receptor

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