Dawn of a New RAMPage

Serafin, Donald; Harris, Natalie R.; Nielsen, Natalie R; Mackie, Duncan I.; Caron, Kathleen M.

doi:10.1016/j.tips.2020.01.009

Cited by 32 publications

(30 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAMPs and CLR associate in the endoplasmic reticulum and are trafficked to the plasma membrane (PM) since neither can efficiently migrate to the cell surface alone. Beyond their roles as molecular chaperones, RAMPs can modulate ligand binding, G protein coupling, downstream effector recruitment and receptor internalisation and recycling of other class B1 GPCRs including; calcitonin receptor (CTR); parathyroid hormone 1 receptor (PTH1R); parathyroid hormone 2 receptor (PTH2R); secretin receptor (SCTR); GCGR; corticotrophin releasing factor receptor 1 (CRFR1) and; vasoactive intestinal polypeptide receptor 1 (VPAC1R) [15][16][17][18][19] . A recent study demonstrated that the majority of class B1 GPCRs are capable of interacting with RAMPs 20 .…”

Section: Introductionmentioning

confidence: 99%

RAMPs regulate signalling bias and internalisation of the GIPR

Harris

Mackie²,

Pawlak³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Gastric inhibitory polypeptide (GIP) receptor is a class B1 GPCR, that responds to GIP and physiologically potentiates glucose-stimulated insulin secretion. Like most class B1 GPCRs, GIPR has been shown to interact with RAMPs, yet the effects of RAMPs on its signalling and trafficking remain poorly understood. We demonstrate that RAMPs modulate G protein activation and GIPR internalisation profiles. RAMP3 reduced GIPR Gs activation and cAMP production but retained GIPR at the cell surface, and this was associated with prolonged ERK1/2 phosphorylation and β-arrestin association. By contrast, RAMP1/2 reduced Gq/11/15 activation of the GIPR. Through knockout mice studies, we show that RAMP1 is important to the normal physiological functioning of GIPR to regulate blood glucose levels. Thus, RAMPs act on G protein/β-arrestin complexes, having both acute and chronic effects on GIPR function, while this study also raises the possibility of a more general role of RAMP3 to enhance GPCR plasma membrane localisation.

show abstract

Section: Introductionmentioning

confidence: 99%

RAMPs regulate signalling bias and internalisation of the GIPR

Harris

Mackie²,

Pawlak³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Molecular modeling and simulation methods have become a standard tool to visualize and mimic various physiological systems and to study cellular phenomena in multidimensional approaches. Till date, the role of RAMPs in class B GPCRs are broadly investigated 11,[16][17][18][19] , and there are various experimental studies performed for the neuropeptide-cell signaling and activation mechanisms 16,[19][20][21][22] , as well as the receptor stability and ligand selectivity 9,23,24 . The release of whole structural domains of the human CGRP receptor (CLR + RAMP1) with bound CGRP neuropeptide and in complex with the Gs-protein heterotrimer by Liang et al is expected to give great momentum to the in silico studies in this area.…”

Section: Introductionmentioning

confidence: 99%

Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of CGRPR heterodimer

Aksoydan

Durdağı

2021

Preprint

View full text Add to dashboard Cite

The release of the neuropeptide of calcitonin gene-related peptide (CGRP) plays a key role in the mechanisms of migraine pathology and pain perception as it causes vasodilatation, neurogenic inflammation, mast cell degranulation, sensory signal activation and peripheral sensitivity. Although the findings on the effectiveness of CGRP-targeted therapies in migraine provide new information about the pathophysiology of migraine, questions remain on how the CGRP mechanisms fit into the overall migraine theory. The cryo-EM structure of Gs-protein complexed human CGRP receptor (CGRPR) with bound endogenous CGRP neuropeptide paved the way of understanding the insights into the CGRP receptor function. With several molecular modeling approaches, molecular dynamics (MD) simulations and post-MD analyzes, we aimed to investigate the importance of RAMP1 in the stability of calcitonin receptor-like receptor (CLR). Moreover, we compared the binding modes of the CGRP neuropeptide and CGRPR antagonists (i.e., telcagepant and rimegepant) within the presence or absence of RAMP1. We also investigated the global and local effects of bound molecules on CGRPR as well as their effects on the CLR-RAMP1 interaction interfaces. Results showed that although these molecules stay stable at the ectodomain binding site, they can also bind to the orthosteric ligand binding pocket and form the crucial interactions occurred in the CGRP agonism, which may be interpreted as non-specificity of the ligands, however, most of these interactions at orthosteric site are not sustainable or weak. Particularly, RAMP1 may also be important for the stability of TM domain of CLR hereby stabilizing the orthosteric binding pocket.

show abstract

“…FITC-AC413(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) or FITC-sCT(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) binding to Endo H-treated CTR ECD coincubated with glycan-free RAMP2 ECD 100 M A) Selective FITC-AC413(6-25) binding to Endo H-treated CTR ECD coincubated with RAMP2 ECD 100 M compared to its binding to Endo H-treated CTR ECD alone. Representative curves were shown from three independent experiments.…”

mentioning

confidence: 99%

“…Effects of the Asn-linked GlcNAc of CTR N130 on FITC-AC413(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) or FITC-sCT(22-32) binding for the RAMP2 ECD:CTR ECD complex.A) FITC-AC413(6-25) binding for Endo H-treated CTR ECD WT or N130D and glycan-free CTR ECD that were coincubated with glycan-free RAMP2 ECD 100 M. Glycan-free CTR ECD produced from E.coli was used for the formation of the RAMP2 ECD:CTR ECD complex without any N-glycans.…”

mentioning

confidence: 99%