RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

McLatchie, Linda M.; Fraser, Neil; Main, Martin J.; Wise, Alan; Brown, James R.; Thompson, Nicola; Solari, Roberto; Lee, Melanie G.; Foord, Steven M.

doi:10.1038/30666

Cited by 1,974 publications

(1,779 citation statements)

References 26 publications

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“…The CGRP system can also be augmented by increased receptor signaling. The CGRP receptor is a trimer of proteins, consisting of the CLR and 2 accessory proteins, receptor activity-modifying protein 1 and RCP (45). RCP enhances signaling at the CGRP receptor (26), and in previous studies, expression of RCP correlated with increased CGRP efficacy during gestation (46).…”

Section: Discussionmentioning

confidence: 89%

Intraarticular induction of interleukin‐1β expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain

Lai

Shaftel

Miller

et al. 2006

Arthritis & Rheumatism

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Objective. To examine the effects of intraarticular induction of interleukin-1␤ (IL-1␤) expression in adult mice.Methods. We used somatic mosaic analysis in a novel transgenic mouse with an inducible IL-1␤ transcription unit. Transgene activation was induced by Cre recombinase in the temporomandibular joints (TMJs) of adult transgenic mice (conditional knockin model). The effects of intraarticular IL-1␤ induction were subsequently evaluated at the cellular, histopathologic, and behavioral levels. Osteoarthritis (OA) manifests as a slowly progressing debilitating disease that affects one or more joints of the body. Clinical symptoms include pain, dysfunction, and swelling and enlargement of the joints. The primary pathologic features of OA are fibrillation and loss of articular cartilage, accompanied by remodeling of subchondral bone. OA seems to be a node of convergence for a number of potentially independent pathologic processes that, ultimately, can lead to joint dysfunction and pain (1). Although the role of inflammation in OA has been long debated (2), recent evidence now confirms proinflammatory cytokines as mediators in this disease (3). For example, the catabolism of OA cartilage is thought to involve the action of proinflammatory cytokines such as interleukin-1 (IL-1)

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Section: Discussionmentioning

confidence: 89%

Intraarticular induction of interleukin‐1β expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain

Lai

Shaftel

Miller

et al. 2006

Arthritis & Rheumatism

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“…The receptor for CGRP consists of a complex of a seven transmembrane-spanning protein, calcitonin receptor-like receptor (CLR), a single transmembrane-spanning protein designated receptor activity modifying protein 1 (RAMP1) [8] and an intracellular protein, receptor component protein (RCP) [9]. Recently, CGRP antagonists have been developed with clinical efficacy for the treatment of acute migraine attacks [10-12].…”

Section: Introductionmentioning

confidence: 99%

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

2011

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BackgroundCalcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central to regions in the brainstem with Aδ- and C-fibers; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that processes nociceptive information from the trigeminovascular system, such as the spinal trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level, using a set of newly well characterized antibodies. In addition, double-stainings with CGRP and myelin basic protein (MBP, myelin), synaptophysin (synaptic vesicles) or IB4 (C-fibers in general) were performed.ResultsIn the STN, the highest density of CGRP immunoreactive fibers were found in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP was expressed in fibers of laminae I and II. The CGRP staining was similar in rat, except for CGRP positive neurons that were found close to the central canal. In C1, the receptor components were detected in laminae I and II, however these fibers were distinct from fibers expressing CGRP as verified by confocal microscopy.ConclusionsThis study demonstrates the detailed expression of CGRP and its receptor components within STN in the brainstem and in the spinal cord at C1-level, and shows the possibility of CGRP acting postjunctionally in these areas putatively involved in primary headaches.

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“…First, similar to many other membrane proteins, receptors must be correctly folded in order to pass the ER quality control mechanism [3,4]. Second, export from the ER and further transport to the cell surface of some G protein-coupled receptors requires specific accessory proteins or chaperones [5][6][7][8]. Interaction of the receptors with chaperones may regulate correct folding/assembly of the receptors within the ER and facilitates receptor transport from the ER and on to the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

Zhou

Filipeanu

Duvernay

et al. 2006

Cellular Signalling

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We previously demonstrated that the α 2B -adrenergic receptor mutant, in which the F(x) 6 IL motif in the membrane-proximal carboxyl terminus were mutated to alanines (α 2B -ARm), is deficient in export from the endoplasmic reticulum (ER). In this report, we determined if α 2B -ARm could modulate transport from the ER to the cell surface and signaling of its wild-type counterpart. Transient expression of α 2B -ARm in HEK293T cells markedly inhibited cell-surface expression of wild-type α 2B -AR, as measured by radioligand binding. Subcellular localization demonstrated that α 2B -ARm trapped α 2B -AR in the ER. The α 2B -AR was shown to form homodimers and heterodimers with α 2B -ARm as measured by co-immunoprecipitation of the receptors tagged with green fluorescent protein and hemagglutinin epitopes. In addition to α 2B -AR, the transport of α 2A -AR and α 2C -AR to the cell surface was also inhibited by α 2B -ARm. Furthermore, transient expression of α 2B -ARm significantly reduced cell-surface expression of endogenous α 2 -AR in NG108-15 and HT29 cells. Consistent with its effect on α 2 -AR cell-surface expression, α 2B -ARm attenuated α 2A -AR-and α 2B -AR-mediated ERK1/2 activation. These data demonstrated that the ER-retained mutant α 2B -ARm conferred a dominant negative effect on the cell-surface expression of wild-type α 2 -AR, which is likely mediated through heterodimerization. These data indicate a crucial role of ER export in the regulation of cell-surface targeting and signaling of G protein-coupled receptors.

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RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

Cited by 1,974 publications

References 26 publications

Intraarticular induction of interleukin‐1β expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain

Intraarticular induction of interleukin‐1β expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

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