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Use of Intrinsic Relative Activity to determine agonist dependent G‐protein signaling at the M4 muscarinic receptor
Author(s) -
Figueroa Katherine W,
Ehlert Frederick J
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.a424-b
Subject(s) - agonist , muscarinic acetylcholine receptor , oxotremorine , carbachol , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m3 , receptor , g protein , chemistry , partial agonist , intrinsic activity , muscarinic agonist , functional selectivity , g protein coupled receptor , pharmacology , biology , biochemistry
Analytical methods to evaluate agonist pharmacological properties across various assay types are currently limited to individual evaluation of parameters such as EC 50 and E max . Our lab has developed a novel measure named intrinsic relative activity (RA i ) to characterize a compound's receptor dependent properties. RA i is defined as the product of observed affinity and intrinsic efficacy of an agonist calculated in comparison to a standard agonist. In evaluating this new method, we analyzed the activity of muscarinic agonists in a model of M 4 receptor‐G‐protein promiscuity to elucidate whether there is agonist directed signaling for this receptor. RA i values were calculated for a series of muscarinic agonists tested in cell‐based assays enabling M 4 to signal via G i , G s and G α15 proteins. Preliminary data suggests certain muscarinic agonists, e.g., McN‐A‐343 and R‐aceclidine, stimulate G i ‐proteins more effectively than alternate G s and G α15 . In contrast, compared to a carbachol standard oxotremorine‐M and S‐aceclidine are capable of transducing agonist responses effectively across all G‐proteins tested. Thus, RA i is a valuable tool for evaluating G‐protein promiscuity at the M 4 receptor. Supported by NIH grant 69829 (Frederick J. Ehlert) and Pre‐Doctoral Fellowship from The PhRMA Foundation (Katherine W. Figueroa).