title: Remodeling of inward rectifying K(+) currents in rat atrial myocytes by overexpression of A(1)-adenosine receptors.
abstract: In rat atrial myocytes GIRK (Kir3) channels can be activated by acetylcholine and adenosine via M(2) and A(1) receptors coupled to Pertussis-toxin-sensitive G proteins, such as M(2)R or A(1)R. Owing to the lower density of A(1)R, the amplitude of current activated by a saturating concentration (10 μM) of Ado (I(K(Ado))) amounts to about 40% of maximum I(K(ACh)). Adenovirus-driven overexpression of A(1)R results in an increase in I(K(Ado)). In a fraction of A(1)R-overexpressing cells, both ACh and Ado failed to activate GIRK channels. These cells had a large constitutive Ba(2+)-sensitive inward rectifying background K(+) current, which was insensitive to the GIRK channel inhibitor tertiapin (200 nM), suggesting this current component to be carried by I(K1) (Kir) channels. This effect of A(1)R overexpression was reduced by treatment (48 h) with the A(1)R antagonist DPCPX. siRNA-mediated knockdown of Kir2.1, simultaneously with A(1)R overexpression, substantially reduced I(K1). The mechanisms underlying the upregulation of functional I(K1) channels involve activation of the phosphatidylinositol 3-kinase (Pi3K)/Akt (protein kinase B) pathway. Kir2.1 transcripts are not increased in myocytes overexpressing A(1)R. These data demonstrate that manipulation of the expression level of a G protein-coupled receptor has unpredictable effects on functional expression of proteins that are supposed to be unrelated to the pathway controlled by that GPCR.
authors.affiliation: Abteilung für Zelluläre Physiologie, Ruhr-Universität Bochum, Universitätstrasse 150, 44780 Bochum, Germany. Cecile.Kienitz@rub.de
authors.forename: M-C
authors.initials: MC
authors.lastname: Kienitz
authors.forename: C
authors.initials: C
authors.lastname: Littwitz
authors.forename: K
authors.initials: K
authors.lastname: Bender
authors.forename: L
authors.initials: L
authors.lastname: Pott
mesh_terms: D000818:Animals; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006325:Heart Atria / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D051381:Rats; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D043682:Receptor, Adenosine A1