Disease relevance of CALCRL

• Reverse transcription-PCR and Western blotting indicated that pancreatic cancer cells expressed only ADMR but not CRLR [1].
• To obtain structural and functional information on the Nt-CRLR, we cloned and expressed the Nt-CRLR as a fusion protein in Escherichia coli [2].
• The CGRP receptor can couple via pertussis toxin sensitive and insensitive G proteins [3].
• The present study demonstrates for the first time that AM and its receptor component (CRLR/RAMP2) mRNAs were concomitantly expressed in various adipose tissues, whose tissue-specific upregulation was induced during the development of obesity [4].
• Our results showed that ADM receptor components-the mRNA and proteins of calcitonin receptor-like receptor (CALCRL) and receptor activity modifying proteins (RAMPs)-were expressed by human choriocarcinoma JAr cells and first-trimester cytotrophoblast HTR-8/SV neo cells [5].

High impact information on CALCRL

• Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented [6].
• RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor [7].
• RAMPs are required to transport CRLR to the plasma membrane [7].
• Both pain parameters were sensitive to morphine, U50488H, trimebutine, neonatal capsaicin treatment, and the CGRP receptor antagonist but not to the neurokinin 1 receptor antagonist [8].
• The perils of using the human genome sequence: lessons from CALCRL [9].

Chemical compound and disease context of CALCRL

• We examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS) [10].
• The data show that CGRP increases intracellular free Ca2+concentration but is not coupled to adenylate cyclase in CGRP receptor-positive OHS-4 osteosarcoma cells, suggesting that CGRP induces downstream events driven by phospholipase C in these cells [11].
• Calcitonin gene-related peptide (CGRP) increases intracellular free Ca2+ concentrations but not cyclic AMP formation in CGRP receptor-positive osteosarcoma cells (OHS-4) [11].
• This review will discuss the therapeutic potential of olcegepant, the first non-peptide CGRP receptor antagonist available for human studies, within the context of current neurovascular theories on migraine pathology [12].
• And this beneficial effect of heat stress on HUVECs was inhibited by capsazepine or CGRP(8-37), the CGRP receptor antagonist [13].

Biological context of CALCRL

• Contrary to observations in mammalian cells, the glycosylation of CRLR was not affected by the presence of RAMPs in yeast, indicating that glycosylation of CRLR is not the prime determinant of ligand specificity [14].
• In vivo studies demonstrated that intermedin treatment led to blood pressure reduction in both normal and spontaneously hypertensive rats via interactions with the CRLR/RAMP receptor complexes [15].
• Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy [16].
• The CRLR receptor phenotype can be determined by coexpression of CRLR with one of the three-receptor activity modifying proteins (RAMPs) [17].
• Reverse transcription (RT)-polymerase chain reaction (PCR) allowed the detection of pADM, L1-R and CRLR mRNAs in cultured human skin keratinocytes and fibroblasts [18].

Anatomical context of CALCRL

• The sequence is unrelated to consensus endoplasmic reticulum retention/retrieval motives and overridden by the presence of the hCRLR [19].
• Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat [20].
• CLR and RAMP1 were detected in perivascular nerves and arterial smooth muscle [20].
• MATERIALS AND METHODS: Expression of CGRP receptor components on CD34(+) cells, peripheral blood granulocytes, and in vitro differentiated CD34(+) cells was analyzed at the mRNA level and by measuring the signaling capacity of the receptor [21].
• CLR was detected at low levels in the soma of enteric, dorsal root ganglia (DRG), and spinal neurons [20].

Associations of CALCRL with chemical compounds

• Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer [22].
• Whichever RAMP protein was co-expressing with CRLR, the ligand binding was sensitive to tunicamycin [23].
• This internalization was strongly inhibited by hypertonic medium (0.45 m sucrose) and paralleled localization of rhodamine-labeled transferrin, suggesting that CRLR endocytosis occurred predominantly through a clathrin-dependent pathway [24].
• Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8-37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor (Nomega-nitro-l-arginine methyl ester) [25].
• CRLR mRNA levels were half-reduced with the two lowest doses of dexamethasone (10(-10) and 10(-9) M), but increased from 10(-8) to 10(-7) M [26].

Physical interactions of CALCRL

• By contrast, deletion of the C-tail from hRAMP2 disrupted transport of hCRLR to the cell surface, resulting in significant reductions in (125)I-hAM binding and evoked cAMP accumulation [27].
• RAMP 1-transported CRLR is a calcitonin gene-related peptide (CGRP) receptor [28].
• RAMP2- and RAMP3-transported CRLR receptors act as AM-specific receptors [29].
• Analysis of CRLR mutants in which Gln was substituted for selected Asn residues showed that glycosylation of Asn123 is required for both the binding of adrenomedullin and the transduction of its signal [23].
• Similarly, in HEK293 EBNA cells constitutively expressing RAMP1/CRLR receptor complex CGRP binding was remarkably inhibited [23].

Regulatory relationships of CALCRL

• CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1 [30].
• TNF-alpha induced time- and dose-dependent decreases in the expression of CRLR and RAMP1/2 mRNAs, thereby diminishing AM-evoked cAMP production [31].
• 4. h-alpha CGRP(8-37) and BIBN4096BS concentration-dependently inhibited cAMP formation evoked by CGRP receptor agonists [32].
• Aim: To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin [33].
• CGRP-mediated JNK-activation was inhibited by CGRP receptor antagonist, CGRP8-37, confirming that this is a receptor-mediated event [34].

Other interactions of CALCRL

• Thus, the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization [27].
• We review here tools that are currently available in order to target each NP, NPY and CT/CGRP receptor subtype and establish their respective pathophysiological relevance [35].
• The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive adrenomedullin receptor [36].
• Co-expression of the CL receptor and RAMP1, formed a CGRP receptor, as in mammals [37].
• The role of RAMPs beyond their interaction with CRLR, a class II G protein-coupled receptor, is unclear [28].

Analytical, diagnostic and therapeutic context of CALCRL

• Western blot analysis using antibodies raised against the first extracellular loop and the carboxy-terminal part of hCRLR, respectively, detected two major bands corresponding to about 70 and 60 kDa in membrane preparations of cultured endothelial cells and numerous organs including lung, heart ventricle and kidney [38].
• Likewise, confocal microscopy revealed each of the mutant RAMPs translocated hemagglutinin-tagged CLR to the cell surface [39].
• In a reverse transcriptase-polymerase chain reaction assay, bovine CRLR was found to be widely distributed, including in the heart and lungs [40].
• Molecular cloning and pharmacological characterization of bovine calcitonin receptor-like receptor from bovine aortic endothelial cells [40].
• Increases in CRLR and RAMP1 mRNA expressions occurred 4 h after treatment of VSMC with 10(-7) M dexamethasone and no change was found for RAMP2 mRNA [26].

References