Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current

Objective: To define how insulin acts in hypokalemic periodic paralysis (Hy poPP). Background: HypoPP results from point mutations of the skeletal musc le L-type Ca2+ channel. Attacks of flaccid paralysis are associated with hy pokalemia and triggered by insulin. A persistent inward current causes depo larization-induced paralysis. The relationships of the Ca2+ channel mutatio ns to the persistent inward current and how insulin triggers paralytic atta cks are not yet known. Methods: Intercostal muscle fibers from HypoPP and n ormal subjects were studied in vitro at 37 degrees C using two electrodes t o determine action potential thresholds and a three-electrode voltage clamp to study membrane currents. Results: HypoPP fibers were depolarized in bat hing solution with 4 mM K+. Reducing K+ from 4.0 mM to 2.5 or 1.0 mM depola rized HypoPP fibers but hyperpolarized normal fibers. Adding 12 mU/mL of in sulin to bathing fluids increased the depolarization of HypoPP fibers and i ncreased the hyperpolarization of normal fibers. Depolarized HypoPP had inc reased action potential thresholds. The fraction of excitable muscle fibers decreased with increasing fiber depolarization. Blocking Na+ channels or L -type Ca2+ channels did not prevent depolarization induced by hypokalemia o r by insulin. Insulin reduced the conductance of the inward rectifier K+ ch annel for outward-flowing currents. Conclusions: Insulin potentiates depola rization of hypokalemic periodic paralysis (HypoPP) fibers by reducing inwa rd rectifier K+ conductance. The Ca2+ mutations in HypoPP indirectly derang e membrane excitability by altering the function of other membrane channels .