RGD Reference Report - RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents. - Rat Genome Database

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RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents.

Authors: Chen, IS  Furutani, K  Inanobe, A  Kurachi, Y 
Citation: Chen IS, etal., J Physiol. 2014 Mar 15;592(6):1237-48. doi: 10.1113/jphysiol.2013.269803. Epub 2014 Jan 13.
RGD ID: 11064811
Pubmed: PMID:24421355   (View Abstract at PubMed)
PMCID: PMC3961084   (View Article at PubMed Central)
DOI: DOI:10.1113/jphysiol.2013.269803   (Journal Full-text)

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 (KG) 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 KG 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rgs4Ratnegative regulation of potassium ion transmembrane transport  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rgs4  (regulator of G-protein signaling 4)


Additional Information