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Titolo:
G(q/11) and G(i/o) activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: dependence on agonist as well as receptor-subtype
Autore:
Akam, EC; Challiss, RAJ; Nahorski, SR;
Indirizzi:
Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England Univ Leicester Leicester Leics England LE1 9HN er LE1 9HN, Leics, England
Titolo Testata:
BRITISH JOURNAL OF PHARMACOLOGY
fascicolo: 4, volume: 132, anno: 2001,
pagine: 950 - 958
SICI:
0007-1188(200102)132:4<950:GAGAPI>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
GUANINE-NUCLEOTIDE-BINDING; HAMSTER OVARY CELLS; HETEROTRIMERIC G-PROTEINS; GAMMA-S BINDING; REGULATORY PROTEINS; PHARMACOLOGICAL CHARACTERIZATION; CONSTITUTIVE ACTIVATION; SIGNAL-TRANSDUCTION; CARDIAC MEMBRANES; EFFECTOR PATHWAY;
Keywords:
muscarinic receptor; G protein; receptor-G protein coupling; stimulus-dependent trafficking; [S-35]-GTP gamma S; partial agonist;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Challiss, RAJ Univ Leicester, Dept Cell Physiol & Pharmacol, Maurice ShockMed Sci Bldg,Univ Rd, Leicester LE1 9HN, Leics, England Univ Leicester Maurice Shock Med Sci Bldg,Univ Rd Leicester Leics England LE1 9HN
Citazione:
E.C. Akam et al., "G(q/11) and G(i/o) activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: dependence on agonist as well as receptor-subtype", BR J PHARM, 132(4), 2001, pp. 950-958

Abstract

1 Profiles of G protein activation have been assessed using a [S-35]-GTP gammaS binding/immunoprecipitation strategy in Chinese hamster ovary cells expressing either M-1, M-2, M-3 or M-4 muscarinic acetylcholine (mACh) receptor subtypes, where expression levels of M-1 and M-3, or M-2 and M-4 receptors were approximately equal.2 Maximal [S-35]-GTP gammaS binding to G(q 11)alpha stimulated by M-1/M-3 receptors, or G(11-3)alpha stimulated by M-2/M-4 receptors occurred within approximately 2 min of agonist addition. The increases in G(q 11)alpha-[S-35]-GTP gammaS binding after M-1 and M-3 receptor stimulation differed substantially, with M1 receptors causing a 2-3 fold greater increase in [S-35]-GTP gammaS binding and requiring 5 fold lower concentrations of methacholineto stimulate a half-maximal response.3 Comparison of M-2 and M-4 receptor-mediated G(il) (3)alpha[S-35]-GTP gammaS binding also revealed differences, with M-2 receptors causing a greaterincrease in G(il-3)alpha activation and requiring 10 fold lower concentrations of methacholine to stimulate a half-maximal response.4 Comparison of methacholine- and pilocarpine-mediated effects revealed that the latter partial agonist is more effective in activating G(i3)alpha compared to G(il) (2)alpha for both M-2 and M-4 receptors. More marked agonist/partial agonist differences were observed with respect to M-1/M-3-mediated stimulations of G(q) (11)alpha- and G(il-3)alpha-[S-35]-GTP gammaS binding. Whereas coupling to these G alpha subclasses decreased proportionately for M-1 receptor stimulation by these agonists, pilocarpine possesses a greater intrinsic activity at M-3 receptors for G(i)alpha versus G(q 11)alpha activation.5 These data demonstrate that mACh receptor subtype and the nature of the agonist used govern the repertoire of G proteins activated. They also provide insights into how the diversity of coupling can be pharmacologically exploited, and provide a basis for a better understanding of how multiple receptor subtypes can be differentially regulated.

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Documento generato il 27/09/20 alle ore 13:35:07