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McN‐A‐343 directs signaling through the M 2 muscarinic receptor‐Gα 15 complex relative to that of G i
Author(s) -
Ehlert Frederick J,
Griffin Michael T,
Figueroa Katherine W
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a430-a
Subject(s) - carbachol , agonist , oxotremorine , muscarinic acetylcholine receptor , receptor , endocrinology , chemistry , medicine , muscarinic acetylcholine receptor m3 , forskolin , stimulation , biology , biochemistry
We examined whether the coupling of the human M 2 muscarinic receptor to G i and Gα 15 alters agonist activity. We measured agonist‐mediated inhibition of forskolin‐stimulated cAMP accumulation in CHO cells stably expressing the M 2 receptor to assess M 2 receptor signaling through Gα i . The concentration‐response curves were analyzed to estimate a novel measure termed intrinsic relative activity ( RA i ), which is defined as the product of the observed affinity and intrinsic efficacy of the agonist expressed relative to that of the standard carbachol. The RA i values for carbachol, oxotremorine‐M, S‐aceclidine, R‐aceclidine and McN‐A‐343 were 1.0, 4.7, 0.55, 0.086 and 0.0024. The corresponding log mean ± SEM values excluding carbachol were 0.67 ± .026, −0.26 ± .057, −1.06 ± .038 and −2.62 ± .12, respectively. We also examined M 2 receptor signaling through Gα 15 by measuring agonist‐mediated stimulation of phosphoinositide hydrolysis in HEK cells stably expressing Gα 15 and transiently expressing the M 2 receptor. The RA i values for carbachol, oxotremorine‐M, S‐aceclidine, R‐aceclidine and McN‐A‐343 were 1.0, 6.6, 0.75, 0.058 and 0.023. The corresponding log mean ± SEM values excluding carbachol were 0.82 ± .062, −0.13 ± .091, −1.24 ± .069 and −1.63 ± .17. Our results show that the McN‐A‐343‐M 2 receptor‐complex preferentially signals through Gα 15 relative to G i . Supported by NIH Grant GM69829 .