1. The effect of protein kinase activators on cloned inward rectifier channels expressed in Xenopus oocytes was examined using a two-electrode voltage clamp. PKA activators caused no change in K(IR)1.1, K(IR)2.1, or K(IR)2.3 current. The PKC activators phorbol 12-myristate 14-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) inhibited K(IR)2.3 currents, but not K(IR)2.1 or K(IR)1.1 current. This inhibition was blocked by staurosporine. An inactive phorbol ester, 4α-phorbol 12,13-didecanoate (4α-PDD), had no effect on K(IR)2.3. 2. Upon changing solution from 2 to 98 mM K+, K(IR)2.3 but not K(IR)1.1 or K(IR)2.1 currents typically 'ran down' over 5 min to 60-80% of maximum amplitude. Rundown occurred even if PMA was applied before changing to high [K+] solution, indicating that rundown was independent of PKC activity. Rundown was evoked by substituting NMG+ for Na+, showing that it results from low [Na+] and not from high [K+]. These results suggest that K(IR)2.3, but not K(IR)1.1. or K(IR)2.1, is subject to regulation, both by PKC activation and as a consequence of low [Na+](o). The difference in secondary regulation may account for specific responses to PKC stimulation of tissues expressing otherwise nearly identical K(IR) channels.