更新于：2024-11-01

RAMP2

更新于：2024-11-01

基本信息

别名

Calcitonin-receptor-like receptor activity-modifying protein 2、CRLR activity-modifying protein 2、RAMP2

+ [2]

简介

Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.

关联

项与 RAMP2 相关的药物

GND-004

靶点

RAMP2

作用机制

RAMP2 modulators

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RAMP2 相关的临床结果

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100 项与 RAMP2 相关的转化医学

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0 项与 RAMP2 相关的专利（医药）

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383

项与 RAMP2 相关的文献（医药）

2024-07-01·British Journal of Pharmacology

RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB₁, CB₂, GPR18 and GPR55 cannabinoid receptors

Article

作者: Grimsey, Natasha L ; Mountjoy, Kathleen G ; Walker, Christopher S ; Glenn, Nathaniel A K ; Finlay, David B ; Carruthers, Emma R

Background and PurposeReceptor activity‐modifying proteins (RAMPs) and melanocortin receptor accessory proteins (MRAPs) modulate expression and signalling of calcitonin and melanocortin GPCRs. Interactions with other GPCRs have also been reported. The cannabinoid receptors, CB1 and CB2, and two putative cannabinoid receptors, GPR18 and GPR55, exhibit substantial intracellular expression and there are discrepancies in ligand responsiveness between studies. We investigated whether interactions with RAMPs or MRAPs could explain these phenomena.Experimental ApproachReceptors and accessory proteins were co‐expressed in HEK‐293 cells. Selected receptors were studied at basal expression levels and also with enhanced expression produced by incorporation of a preprolactin signal sequence/peptide (pplss). Cell surface and total expression of receptors and accessory proteins were quantified using immunocytochemistry. Signalling was measured using cAMP (CAMYEL) and G protein dissociation (TRUPATH Gα13) biosensors.Key ResultsMRAP2 enhanced surface and total expression of GPR18. Pplss‐GPR18 increased detection of cell surface MRAP2. MRAP1α and MRAP2 reduced GPR55 surface and total expression, correlating with reduced constitutive, but not agonist‐induced, signalling. GPR55, pplss‐CB1 and CB2 reduced detection of MRAP1α at the cell surface. Pplss‐CB1 agonist potency was reduced by MRAP2 in Gα13 but not cAMP assays, consistent with MRAP2 reducing pplss‐CB1 expression. Some cannabinoid receptors increased RAMP2 or RAMP3 total expression without influencing surface expression.Conclusions and ImplicationsMutual influences on expression and/or function for specific accessory protein‐receptor pairings raises the strong potential for physiological and disease‐relevant consequences. Sequestration and/or hetero‐oligomerisation of cannabinoid receptors with accessory proteins is a possible novel mechanism for receptor crosstalk.LINKED ARTICLESThis article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc

2024-05-28·Protein & Cell

Single transmembrane GPCR modulating proteins: neither single nor simple

Article

作者: Zhang, Chao ; Wang, Meng ; Lyu, Jianjun

The discovery of G-protein coupled receptor (GPCR) accessory proteins has fundamentally redefined the pharmacological concept of GPCR signaling, demonstrating a more complex molecular basis for receptor specificity on the plasma membrane and impressionable downstream intracellular cascades. GPCR accessory proteins not only contribute to the proper folding and trafficking of receptors, but also exhibit selectable receptor preferences. The melanocortin receptor accessory proteins (MRAP1 and MRAP2) as well as receptor activity-modifying proteins (RAMPs) are two well-known single transmembrane partners for the regulation of the melanocortin receptors (MC1R-MC5R) and the glucagon receptor (GCGR), respectively. Especially, MRAP family participates in the pathological control of multiple endocrine disorders and RAMPs contribute to the endogenous regulation of glucose homeostasis. However, the precise mechanisms by which the MRAP and RAMP proteins regulate receptor signaling at the atomic resolution remain unknown. Recent progress made in the determination of RAMP2-bound GCGR complexes published on Cell (Krishna Kumar et al., 2023) unraveled the importance of RAMP2 for the promotion of extracellular receptor dynamics leading to cytoplasmic surface inactivation. Moreover, the new findings on Cell Research (Luo et al., 2023) of the adrenocorticotropic hormone (ACTH)-bound MC2R-Gs-MRAP1 complex disclosed the essential role of MRAP1 for MC2R activation and specificity of ligand recognition. In this article, we reviewed a series of key findings of MRAP proteins in the last decade, and the recent structural investigation of MRAP-MC2R and RAMP-GCGR functional complex and the expanded identification of new GPCR partners of MRAP proteins. In-depth understanding of GPCR modulation by single transmembrane accessory proteins will provide valuable insights for the therapeutic drug development to treat multiple GPCR associated human disorders.

2024-05-01·Molecular Pharmacology

Development of a Novel Assay for Direct Assessment of Selective Amylin Receptor Activation Reveals Novel Differences in Behavior of Selective and Nonselective Peptide Agonists

Article

作者: Ballarín-González, Borja ; Christopoulos, George ; Keov, Peter ; Hick, Caroline A ; Sexton, Patrick M ; Wootten, Denise ; Glendorf, Tine

Dual amylin and calcitonin receptor agonists (DACRAs) show promise as efficacious therapeutics for treatment of metabolic disease, including obesity. However, differences in efficacy in vivo have been observed for individual DACRAs, indicating that detailed understanding of the pharmacology of these agents across target receptors is required for rational drug development. To date, such understanding has been hampered by lack of direct, subtype-selective, functional assays for the amylin receptors (AMYRs). Here, we describe the generation of receptor-specific assays for recruitment of Venus-tagged Gs protein through fusion of luciferase to either the human calcitonin receptor (CTR), human receptor activity-modifying protein (RAMP)-1, RAMP1 (AMY₁R), human RAMP2 (AMY₂R), or human RAMP3 (AMY₃R). These assays revealed a complex pattern of receptor activation by calcitonin, amylin, or DACRA peptides that was distinct at each receptor subtype. Of particular note, although both of the CT-based DACRAs, sCT and AM1784, displayed relatively similar behaviors at CTR and AMY₁R, they generated distinct responses at AMY₂R and AMY₃R. These data aid the rationalization of in vivo differences in response to DACRA peptides in rodent models of obesity. Direct assessment of the pharmacology of novel DACRAs at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases. SIGNIFICANCE STATEMENT: Amylin receptors (AMYRs) are important obesity targets. Here we describe a novel assay that allows selective functional assessment of individual amylin receptor subtypes that provides unique insight into the pharmacology of potential therapeutic ligands. Direct assessment of the pharmacology of novel agonists at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases.