Natarajan AR, Han G, Chen SY, Yu P, White RE, Jose PA
The D5 dopamine receptor mediates BKCa channel activation in human coronary artery smooth muscle cells. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Oct 28.
Large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channels hyperpolarize coronary artery smooth muscle cells causing vasorelaxation. Dopamine activates BK(Ca) channels by stimulating D(1)-like receptor-mediated increases in cyclic AMP (cAMP) in porcine coronary artery myocytes. There are two D(1)-like receptors (R), D(1)R and D(5)R. We hypothesize that the specific D(1)-like receptor involved in BK(Ca) channel activation in human coronary artery smooth muscle cells (HCASMC) is the D(5)R, and that activation occurs via cAMP cross-activation of cGMP-dependent protein kinase (PKG), rather than cAMP-dependent protein kinase (PKA). The effects of D(1)-like receptor agonists and antagonists on BK(Ca) channel opening in HCASMC were examined in the presence and absence of PKG/PKA inhibition by cell-attached patch-clamp. In the absence of commercially available ligands specific for D(1)R or D(5)R, D(1)R or D(5)R protein was downregulated by transfecting HCASMC with human D(1)R or D(5)R antisense oligonucleotides respectively: cells transfected with scrambled oligonucleotides and non-transfected HCASMC served as controls. The predominant ion channel conducting outward currents in non-transfected HCASMC was identified as the BK(Ca) channel, which was activated by D(1)-like receptor agonists despite PKA inhibition with KT 5720 (300 nM), but was abolished by inhibiting PKG with KT 5823 (300 nM). D(1)-like receptor agonists activated BK(Ca) channels in all transfected cells except those transfected with D(5)R antisense oligonucleotides. Thus, the dopamine (D(1)-like) receptor mediates activation of BK(Ca) channels in HCASMC by D(5)R, not D(1)R, and via PKG, not PKA. This is the first report of differential D(1)-like receptor regulation of vascular smooth muscle function in human cells.
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