Remodeling of inward rectifying K+ currents in rat atrial myocytes by overexpression of A1-adenosine receptors

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 M2R or A(1)R. Owing to the lower density of A(1)R, the amplitude of current activated by a saturating concentration (10 mu M) 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 Ba2+-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.