Activation of PKC increases Na+-K+ pump current in ventricular myocytes from guinea pig heart

We have previously shown activation of alpha(1)-adrenergic receptors increa ses Na+-K+ pump current (I-p) in guinea pig ventricular myocytes, and the i ncrease Is eliminated by blockers of phosphokinase C (PKC). In this study w e examined the effect of activators of PKC on I-p. Phorbol 12-myristate 13- acetate (PMA), a PKC activator, increased I-p at each test potential withou t shifting its voltage dependence. The concentration required for a half-ma ximal response (K-0.5,) was 6 mu M at 15 nM cytosolic [Ca2+] ([Ca2+](i)) an d 13 nM at 314 nM [Ca2+](i). The maximal increase at either [Ca2+](i) was a bout 30%. Another activator of PKC, 1,2-dioctanoyl-sn-glycerol (diC(8)), in creased I-p similarly. The effect of PMA on I-p was eliminated by the PKC i nhibitor staurosporine, but not by the peptide PKI, an inhibitor of protein kinase A (PKA). PMA and al-adrenergic agonist effects both were sensitive to [Ca2+](i), blocked by PKC inhibitors, unaffected by PKA inhibition, and increased I-p uniformly at all voltages. However, they differed in that alp ha(1)-activation caused a maximum increase of 15% vs 30% via PMA, and alpha (1)-effects were less sensitive to [Ca2+](i) than PMA effects. These result s demonstrate that activation of PKC causes an increase in I-p in guinea pi g ventricular myocytes. Moreover, they suggest that the coupling of alpha(1 )-adrenergic activation to I-p is entirely through PKC, however alpha(1)-ac tivation may be coupled to a specific population of PKC whereas PMA is a mo re global agonist.