The Pharmacology of Adrenomedullin Receptors and Their Relationship to CGRP Receptors

Hay, Debbie L.; Conner, Alex C.; Howitt, Stephen G; Smith, David M.; Poyner, David R.

doi:10.1385/jmn:22:1-2:105

Cited by 86 publications

(55 citation statements)

References 41 publications

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“…3B). Because the ADM receptor, composed of CRLR and RAMP-2, is more sensitive to ADM 22-52 , whereas the CRLR-RAMP-3 receptor complex shows a clear preference for CGRP 8-37 -induced antagonism (Hay et al, 2004), these results suggest that the CRLR-RAMP-2 receptor complex plays the predominant role in mediating ADM's effects in the hypothalamic neurons.…”

Section: Resultsmentioning

confidence: 86%

“…To characterize the effects of ADM on [Ca 2ϩ ] i and NO production, MEM containing ADM (1 or 10 nM; American Peptide Company, Sunnyvale, CA) was injected into the chamber; the solution was washed away with MEM 5 min later. To determine which receptor mediates ADM's effects, cells were first exposed to 10 nM ADM for 5 min, washed with MEM, and then pretreated for 10 min with 10 nM ADM 22-52 , a putative antagonist for ADM receptor composed of CRLR and RAMP-2 or 10 nM CGRP 8-37 , a putative antagonist for CGRP receptor or ADM receptor composed of CRLR and RAMP-3 (Hay et al, 2004). These pretreatments were then followed by 5-min applications of 10 nM ADM in the presence of respective antagonists.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Krukoff²

2007

Mol Pharmacol

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Adrenomedullin (ADM) in the brain plays important roles in the maintenance of homeostasis. Although in vivo evidence has suggested that nitric oxide (NO) mediates ADM's effects in the brain, mechanisms for ADM stimulation of NO production in neurons have not been identified. In the present study, primary hypothalamic neurons were used to characterize ADM-induced NO production and to study the underlying mechanisms. Using Calcium Orange/4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein fluorescence live cell imaging, we found that ADM (1 or 10 nM, 5 min) significantly elevated [Ca 2ϩ ] i and NO production in a concentration-dependent manner. Ca 2ϩ and NO responses induced by 10 nM ADM were abolished by pretreatment with 50 M 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), an intracellular Ca 2ϩ chelator, or protein kinase A (PKA) inhibitors 5 M N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) and 50 M Rp-cAMP. Furthermore, the ADM-induced NO production was significantly attenuated by a protein phosphatase 1/2A inhibitor, okadaic acid (OA; 0.1 M), or calcineurin inhibitors, tacrolimus (FK506) (1 M) and cyclosporin A (CsA; 0.1 M). Using Western blotting, we found that ADM significantly decreased phosphorylation of neuronal nitric-oxide synthase (nNOS) at serine 847. This dephosphorylation was inhibited by 0.1 M OA, 1 M FK506, 0.1 M CsA, or 5 M H-89, and attenuated by 50 M BAPTA-AM. These results suggest that, in hypothalamic neurons, ADM elevates [Ca 2ϩ ] i via PKA-associated mechanisms. The PKA/Ca 2ϩ cascade leads to protein phosphatase (PP) 1/PP2A-and calcineurin-mediated dephosphorylation of nNOS. We hypothesize that the Ca 2ϩ increase and nNOS dephosphorylation contribute to activation of nNOS and production of NO in hypothalamic neurons.

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Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Krukoff²

2007

Mol Pharmacol

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“…We have studied the Drosophila orphan GPCR named , 1998;Buhlmann et al, 1999;Christopoulos et al, 1999;Hay et al, 2004). In addition, the receptor component protein (RCP) accessory protein is critical for downstream signaling from the CLR/RAMP complex.…”

mentioning

confidence: 99%

A novel diuretic hormone receptor inDrosophila: evidence for conservation of CGRP signaling

Johnson

Shafer

Trigg

et al. 2005

Journal of Experimental Biology

215

142

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SUMMARY The Drosophila orphan G protein-coupled receptor encoded by CG17415 is related to members of the calcitonin receptor-like receptor (CLR) family. In mammals, signaling from CLR receptors depend on accessory proteins, namely the receptor activity modifying proteins (RAMPs)and receptor component protein (RCP). We tested the possibility that this Drosophila CLR might also require accessory proteins for proper function and we report that co-expression of the mammalian or Drosophila RCP or mammalian RAMPs permitted neuropeptide diuretic hormone 31 (DH31) signaling from the CG17415 receptor. RAMP subtype expression did not alter the pharmacological profile of CG17415 activation. CG17415 antibodies revealed expression within the principal cells of Malpighian tubules, further implicating DH31 as a ligand for this receptor. Immunostaining in the brain revealed an unexpected convergence of two distinct DH signaling pathways. In both the larval and adult brain, most DH31 receptor-expressing neurons produce the neuropeptide corazonin, and also express the CRFR-related receptor CG8422, which is a receptor for the neuropeptide diuretic hormone 44 (DH44). There is extensive convergence of CRF and CGRP signaling within vertebrates and we report a striking parallel in Drosophila involving DH44 (CRF) and DH31 (CGRP). Therefore, it appears that both the molecular details as well as the functional organization of CGRP signaling have been conserved.

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“…AM has two specific receptors (AM 1 and AM 2 ) formed by CLR combined with RAMP2 or -3, respectively (Hay et al, 2004). AM also has appreciable affinity for a CGRP receptor, composed of CLR and RAMP1.…”

mentioning

confidence: 99%

Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

Zhao

Bell

Smith

et al. 2005

J Pharmacol Exp Ther

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Adrenomedullin (AM) and intermedin (IMD; adrenomedulln-2) are vasodilator peptides related to calcitonin gene-related peptide (CGRP). The actions of these peptides are mediated by the calcitonin receptor-like receptor (CLR) in association with one of three receptor activity-modifying proteins. CGRP is selective for CLR/ receptor activity modifying protein (RAMP)1, AM for CLR/RAMP2 and -3, and IMD acts at both CGRP and AM receptors. In a model of pressure overload induced by inhibition of nitric-oxide synthase, up-regulation of AM was observed previously in cardiomyocytes demonstrating a hypertrophic phenotype. The current objective was to examine the effects of blood pressure reduction on cardiomyocyte expression of AM and IMD and their receptor components. N -nitro-L-arginine methyl ester (L-NAME) (35 mg/ kg/day) was administered to rats for 8 weeks, with or without concurrent administration of hydralazine (50 mg/kg/day) and hydrochlorothiazide (7.5 mg/kg/day). In left ventricular cardiomyocytes from L-NAME-treated rats, increases (-fold) in mRNA expression were 1.6 (preproAM), 8.4 (preproIMD), 3.4 (CLR), 4.1 (RAMP1), 2.8 (RAMP2), and 4.4 (RAMP3). Hydralazine/hydrochlorothiazide normalized systolic blood pressure (BP) and abolished mRNA up-regulation of hypertrophic markers sk-␣-actin and BNP and of preproAM, CLR, RAMP2, and RAMP3 but did not normalize cardiomyocyte width nor preproIMD or RAMP1 mRNA expression. The robust increase in IMD expression indicates an important role for this peptide in the cardiac pathology of this model but, unlike AM, IMD is not associated with pressure overload upon the myocardium. The concordance of IMD and RAMP1 up-regulation indicates a CGRP-type receptor action; considering also a lack of response to BP reduction, IMD may, like CGRP, have an antiischemic function.

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The Pharmacology of Adrenomedullin Receptors and Their Relationship to CGRP Receptors

Cited by 86 publications

References 41 publications

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

A novel diuretic hormone receptor inDrosophila: evidence for conservation of CGRP signaling

Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

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