Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor

Armour, Susan; Foord, Steven M.; Kenakin, Terrence Peter; Chen, Wen Ji

doi:10.1016/s1056-8719(00)00074-5

Cited by 84 publications

(54 citation statements)

References 31 publications

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“…Many factors alter the potency of agonists at GPCRs; affinity and intrinsic efficacy are receptor-dependent, whereas receptor density and G protein-coupling efficiency are system-dependent (Kenakin, 1997;Armour et al, 1999). In this study, we examined the effect of agonists and antagonists on CT and AMY receptors expressed at similar levels in the same cellular background to reduce system-dependent variables and to allow comparison of relative affinity and intrinsic efficacy of the agents used (Armour et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Hay¹,

Christopoulos²,

et al. 2005

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Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT (a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of ␣CGRP, being a weak agonist at CT (a) , AMY 2(a) , and AMY 3(a) receptors but considerably more potent at AMY 1(a) receptors. Likewise, the linear calcitonin gene-related peptide (CGRP) analogs (Cys(ACM) 2,7 )h␣CGRP and (Cys(Et) 2,7 )h␣CGRP were only effective at AMY 1(a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY 2(a) receptor phenotype; thus, AMY 2(a) was not examined further in this study. The antagonist peptide salmon calcitonin 8-32 (sCT 8-32 ) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY 1(a) over AMY 3(a) receptors. CGRP 8-37 also demonstrated receptor-dependent effects. CGRP 8-37 more effectively antagonized AMY at AMY 1(a) than AMY 3(a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT (a) receptor. Low CGRP 8-37 affinity and agonism by linear CGRP analogs at AMY 1(a) are the classic signature of a CGRP 2 receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT (a) , AMY 1(a) , and AMY 3(a) receptors, providing a means to delineate the physiological significance of these receptors.

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Section: Discussionmentioning

confidence: 99%

“…In this study, we examined the effect of agonists and antagonists on CT and AMY receptors expressed at similar levels in the same cellular background to reduce system-dependent variables and to allow comparison of relative affinity and intrinsic efficacy of the agents used (Armour et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Hay¹,

Christopoulos²,

et al. 2005

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“…Coexpression of receptor activity-modifying protein 3 with the calcitonin receptor has been shown to influence not only agonist potency ranking orders, but also antagonist affinity estimates (Armour et al, 1999). Numerous recent studies have also highlighted the potential for GPCRs to form dimer or higher order oligomer assemblies (see Angers et al, 2002).…”

Section: Tissue-selective Effects Of Muscarinic Antagonists 1261mentioning

confidence: 99%

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Nelson¹,

Gupta²,

Napier³

et al. 2004

J Pharmacol Exp Ther

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Binding and functional affinities of the muscarinic acetylcholine (mACh) receptor antagonists darifenacin, tolterodine, oxybutynin, and atropine were assessed in Chinese hamster ovary (CHO) cells expressing the human recombinant M 2 (CHO-m2) or M 3 (CHO-m3) receptors, and in guinea pig bladder and submandibular gland. In [N-methyl-3 H]scopolamine methyl chloride binding studies in CHO cells, darifenacin displayed selectivity (14.8-fold) for the M 3 versus M 2 mACh receptor subtype. Oxybutynin was nonselective, whereas atropine and tolterodine were weakly M 2 -selective (5.1-and 6.6-fold, respectively). Antagonist functional affinity estimates were determined by the inhibition of agonist-induced [ 3 H]inositol phosphate accumulation in CHO-m3 cells and antagonism of the agonist-induced inhibition of forskolin-stimulated cyclic AMP accumulation in CHO-m2 cells. Darifenacin was the most M 3 -selective antagonist (32.4-fold), whereas oxybutynin, atropine, and tolterodine exhibited lesser selectivity. Functional affinity estimates in guinea pig urinary bladder and submandibular salivary gland using indices of phosphoinositide turnover revealed that oxybutynin, darifenacin, and tolterodine each displayed selectivity for the response in the bladder, relative to that seen in the submandibular gland (9.3-, 7.9-, and 7.4-fold, respectively). In contrast, atropine displayed a similar affinity in both tissues. These data demonstrate that in bladder, compared with submandibular gland from a single species, the mACh receptor antagonists darifenacin, tolterodine, and oxybutynin display selectivity to inhibit agonist-mediated phosphoinositide responses. It is proposed that both responses are mediated via M 3 mACh receptor activation and that differential functional affinities displayed by some, but not all, antagonists are indicative of the influence of cell background upon the pharmacology of the M 3 mACh receptor.The cholinergic nervous system is the major pathway by which bladder contraction is initiated in humans (Andersson, 1993). Molecular techniques have identified five muscarinic acetylcholine (mACh) receptor subtypes (m1-m5), whereas pharmacological data can distinguish only four subtypes, denoted as M 1 to M 4 (Caulfield and Birdsall, 1998). Both M 2 and M 3 mACh receptors have been identified in bladder (detrusor) smooth muscle at the level of mRNA (Yamaguchi et al., 1996) and protein, with quantitative immunoprecipitation demonstrating a 75 to 90% predominance of the M 2 subtype in all species studied (Wang et al., 1995). Roles for the majority M 2 receptor population in the contraction of various smooth muscle types (including bladder detrusor) have been proposed, based upon observations in tissues treated with N-2-chloroethyl-4-piperidinyl diphenylacetate selectively to inactivate the M 3 receptor population. Under these conditions M 2 receptor activation may potentiate M 3 -stimulated contraction (via activation of nonselective cation currents or inhibition of Ca 2ϩ -dependent K ϩ efflux), in addition to ...

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“…Si les complexes RAMP2/CRLR et RAMP3/CRLR forment un R-ADM (Tableau IA), les raisons de l'existence de ces deux complexes ne sont pas établies, les deux types de récepteurs possédant les mêmes caractéristiques [22]. La similitude entre le CRLR et le CTR a suscité des études sur les interactions entre RAMP et CTR, montrant que la co-expression de RAMP1 et de RAMP3 avec un CTR aboutit à un récepteur de l'AMY (TableauIB) [20,23,24] 22-52: antagoniste de l'ADM. r: rat; s: saumon; h: homme.…”

Section: Spécificité De Liaison Du Ligandunclassified

RAMP et récepteurs couplés aux protéines G

Cueille

Garel

2004

Med Sci (Paris)

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Le fonctionnement des récepteurs couplés aux protéines G (RCPG) est connu depuis des décennies, mais un pas important a été franchi récemment, lorsqu'il a été montré que le caractère fonctionnel de certains récepteurs dépendait d'interactions protéiques de nature différente. Le rôle de ces interactions dans la localisation des RCPG et la transduction du signal a fait l'objet d'une revue récente [1]. En 1998, la découverte des RAMP (receptor activity-modifying protein), que l'on peut considérer comme des chaperons moléculaires pour les récepteurs du CGRP (calcitonin gene-related peptide) et de l'adrénomédulline (ADM), a modifié notre conception du fonctionnement des RCPG. L'interaction des RAMP avec les RCPG n'est observée, à ce jour, que dans le cas des récepteurs de classe II, c'est-à-dire des récepteurs de la calcitonine (CTR), de l'hormone parathyroïdienne (RPTH), du glucagon et du VIP/PACAP ou R-VPAC1. Les récepteurs du CGRP et de l'ADM

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Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor

Cited by 84 publications

References 31 publications

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

RAMP et récepteurs couplés aux protéines G

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Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor

Cited by 84 publications

References 31 publications

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M3-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

RAMP et récepteurs couplés aux protéines G

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Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland