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RGS4 regulates partial agonism of the M2 muscarinic receptor‐activated K + currents
Author(s) -
Chen IShan,
Furutani Kazuharu,
Inanobe Atsushi,
Kurachi Yoshihisa
Publication year - 2014
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2013.269803
Subject(s) - agonism , muscarinic acetylcholine receptor , partial agonist , chemistry , receptor , neuroscience , pharmacology , agonist , medicine , biology , biochemistry , politics , political science , law
Key points Partial agonists produce a smaller response than full agonists even at 100% receptor occupancy. In G‐protein‐coupled receptor signalling, the submaximal efficacy of partial agonists is determined by the conformational change of the agonist–receptor complex, which reduces effector activation. However, it remains unclear whether the regulator of G‐protein signalling (RGS) proteins contribute to the partial agonism. By analysing the M2 muscarinic receptor (M2R)‐activated G‐protein‐gated K + inwardly rectifying (K G ) currents in a Xenopus oocyte expression system, pilocarpine acted as a partial agonist in the presence of RGS4, as it did in rat atrial myocytes, while it acted like the full agonist ACh in the absence of RGS4. Functional couplings within the agonist–M2R complex/G‐protein/RGS4 system controlled the relative efficacy of the agonists. Our findings help us to understand the molecular components and mechanism underlying the partial agonism of M2R‐mediated physiological responses.Abstract Partial agonists are used clinically to avoid overstimulation of receptor‐mediated signalling, as they produce a submaximal response even at 100% receptor occupancy. The submaximal efficacy of partial agonists is due to conformational change of the agonist–receptor complex, which reduces effector activation. In addition to signalling activators, several regulators help control intracellular signal transductions. However, it remains unclear whether these signalling regulators contribute to partial agonism. Here we show that regulator of G‐protein signalling (RGS) 4 is a determinant for partial agonism of the M2 muscarinic receptor (M2R). In rat atrial myocytes, pilocarpine evoked smaller G‐protein‐gated K + inwardly rectifying (K G ) currents than those evoked by ACh. In a Xenopus oocyte expression system, pilocarpine acted as a partial agonist in the presence of RGS4 as it did in atrial myocytes, while it acted like a full agonist in the absence of RGS4. Functional couplings within the agonist–receptor complex/G‐protein/RGS4 system controlled the efficacy of pilocarpine relative to ACh. The pilocarpine–M2R complex suppressed G‐protein‐mediated activation of K G currents via RGS4. Our results demonstrate that partial agonism of M2R is regulated by the RGS4‐mediated inhibition of G‐protein signalling. This finding helps us to understand the molecular components and mechanism underlying the partial agonism of M2R‐mediated physiological responses.