Dopamine (DA) inhibits rodent proximal tubule Na⁺,K⁺-ATPase via stimulation of protein kinase C (PKC). However, direct stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) results in increased Na⁺,K⁺-ATPase. LY333531, a specific inhibitor of the PKC-β isoform, prevents PMA-dependent activation of Na⁺,K⁺-ATPase, but has no effect on DA inhibition of this activity. A similar result was obtained with a PKC-β inhibitor peptide. Concentrations of staurosporine, that inhibits PKC-ζ, prevent DA-dependent inhibition of Na⁺,K⁺-ATPase and a similar effect was obtained with a PKC-ζ inhibitor peptide. Thus, PMA-dependent stimulation of Na⁺,K⁺-ATPase is mediated by activation of PKC-β, whereas inhibition by DA requires activation of PKC-ζ.