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Titolo:
Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand
Autore:
Yang, YK; Dickinson, C; Lai, YM; Li, JY; Gantz, I;
Indirizzi:
Univ Michigan, Med Ctr, Dept Surg, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 , Dept Surg, Ann Arbor, MI 48109 USA Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 Dept Pediat, Ann Arbor, MI 48109 USA
Titolo Testata:
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
fascicolo: 6, volume: 281, anno: 2001,
pagine: R1877 - R1886
SICI:
0363-6119(200112)281:6<R1877:FPOAAS>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
STIMULATING-HORMONE-RECEPTOR; MELANOCORTIN RECEPTORS; ALPHA-MELANOTROPIN; TRANSGENIC MICE; CAUSES OBESITY; HUMAN HOMOLOG; MOUSE; GENE; BINDING; ANTAGONIST;
Keywords:
melanocortin receptors; alpha-[Nle(4),D-Phe(7)]melanocyte-stimulating hormone; agouti-related protein; obesity; pigmentation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Gantz, I 6504 MSRB I,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA 6504 MSRBI,1150 W Med Ctr Dr Ann Arbor MI USA 48109 I 48109 USA
Citazione:
Y.K. Yang et al., "Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand", AM J P-REG, 281(6), 2001, pp. R1877-R1886

Abstract

Agouti signaling protein (ASIP), the human (h) homolog of agouti, is an endogenous melanocortin peptide antagonist. To date, characterization of thisprotein has been performed with recombinant protein only and without the availability of an ASIP/agouti radioligand. In this report we describe the functional characteristics of a chemically synthesized truncated ASIP variant, ASIP-[90-132 (L89Y)], and the binding characteristics of its cognate radioligand, I-125-ASIP-[90-132 (L89Y)]. Similar to full-length recombinant ASIP/agouti, ASIP-[90-132 (L89Y)] was a potent inhibitor of alpha -melanocyte-stimulating hormone cAMP generation at the cloned human melanocortin receptor (hMCR) subtypes hMC1R and hMC4R. It also displayed a lesser degree of inhibition at the hMC3R and hMC5R. However, ASIP-[90-132 (L89Y)] was found to be less potent than full-length recombinant ASIP and, surprisingly, only exhibited weak inhibitory activity at the hMC2R. In competition binding assays with the radioligand I-125-ASIP-[90-132 (L89Y)], ASIP-[90-132 (L89Y)] displayed a hierarchy of binding affinity that roughly paralleled its rank order of inhibitory potency at the various MCR subtypes, i.e., hMC1R approximate to hMC4R > hMC3R approximate to hMC5R > hMC2R. Structure-activity studies revealed that ASIP-[90-132 (L89Y)] possessed greater pharmacological potency than either the further truncated ASIP variants ASIP-(116-132) or cyclo(CRFFRSAC). Interestingly, the latter molecules were both weak agonists at the hMC1R. These studies further support the concept that ASIP/agouti inhibits melanocortin action by directly binding to target MCRs and provide additional insight into the structural requirements for maximal inhibitory potency.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/10/20 alle ore 09:23:05