Different Subtypes of α1-Adrenoceptor Modulate Different K+ Currents via Different Signaling Pathways in Canine Ventricular Myocytes

Abstract

Multiple subtypes (α1A, α1B, and α1D) of α1-adrenoreceptors (α 1ARs) co-exist in the heart and mediate a variety of cellular functions. We studied α1AR modulation of inward rectifier (IK1) and transient outward (Ito) K+ currents in canine ventricular myocytes. Phenylephrine at 10 μM depressed only I to without affecting IK1 and at 100 μ inhibited both Ito and IK1. The effect of phenylephrine on I to was abolished by (+)niguldipine (10 nM) to inhibit α 1A AARs but not by chloroethyclonidine (10 μM) to inactivate α1BARs nor by BMY-7378 to antagonize α1DARs. In contrast, phenylephrine inhibition of IK1 was reversed only by BMY-7378 (1 nM). PDD (100 nM, phorbol ester activator of protein kinase C (PKC)) simulates and bisindolylmaleimide (50 nM, PKC inhibitor) weakens phenylephrine modulation of Ito but not IK1. Ca 2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 and inhibitor peptides abolished the effects of phenylephrine on I K1. Enhancement of PKC or CaMKII activities was seen in α 1aAR- or α1dAR-transfected HEK293 cells and in myocytes pretreated with 10 or 100 μM phenylephrine, respectively. Our data suggest that different subtypes of α1ARs selectively modulate different cardiac K+ currents via different signal transduction mechanisms; α1AARs mediate Ito regulation via PKC, and α1DARs mediate IK1 regulation via CaMKII.