ATP-sensitive potassium (KATP) channels activate under metabolic stress to protect neurons and cardiac myocytes. However, excessive channel activation may cause arrhythmia in the heart and silence neurons in the brain. Here, we report that PKC-mediated downregulation of KATP channel number, via dynamin-dependent channel internalization, can act as a brake mechanism to control KATP activation. A dileucine motif in the pore-lining Kir6.2 subunit of KATP, but not the site of PKC phosphorylation for channel activation, is essential for PKC downregulation. Whereas KATP activation results in a rapid shortening of the action potential duration (APD) in metabolically inhibited ventricular myocytes, adenosine receptor stimulation and consequent PKC-mediated KATP channel internalization can act as a brake to lessen this APD shortening. Likewise, in hippocampal CA1 neurons under metabolic stress, PKC-mediated, dynamin-dependent KATP channel internalization can also act as a brake to dampen the rapid decline of excitability due to KATP activation.