RESTORATION OF INACTIVATION AND BLOCK OF OPEN SODIUM-CHANNELS BY AN INACTIVATION GATE PEPTIDE

Inactivation of sodium channels terminates the sodium current responsi ble for initiation of action potentials in excitable cells. A hydropho bic sequence (isoleucine-phenylalanine-methionine, IFM), located in th e inactivation gate segment connecting homologous domains III and IV o f the sodium channel alpha subunit, is required for fast inactivation. A synthetic peptide containing the IFM sequence (acetyl-KIFMK-amide) restores fast inactivation to mutant sodium channels having a defectiv e inactivation gate and to wild-type sodium channels having inactivati on slowed by alpha-scorpion toxin. This peptide also competes with the intrinsic inactivation particle and binds to and blocks open sodium c hannels in a voltage- and frequency-dependent manner. A peptide (acety l-KIQMK-amide) containing a mutation that prevents fast inactivation i s not effective in restoring inactivation or in blocking open sodium c hannels. The results support the hypothesis that the sequence IFM serv es as the inactivation particle of the sodium channel and suggest that it enters the intracellular mouth of the pore and occludes it during the process of inactivation.