R L Ruff1. 1. Department of Neurology, Case Western Reserve University School of Medicine, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, University Hospitals of Cleveland, OH 44106, USA.
Abstract
OBJECTIVE: To define how insulin acts in hypokalemic periodic paralysis (HypoPP). BACKGROUND: HypoPP results from point mutations of the skeletal muscle L-type Ca2+ channel. Attacks of flaccid paralysis are associated with hypokalemia and triggered by insulin. A persistent inward current causes depolarization-induced paralysis. The relationships of the Ca2+ channel mutations to the persistent inward current and how insulin triggers paralytic attacks are not yet known. METHODS: Intercostal muscle fibers from HypoPP and normal subjects were studied in vitro at 37 degrees C using two electrodes to determine action potential thresholds and a three-electrode voltage clamp to study membrane currents. RESULTS: HypoPP fibers were depolarized in bathing solution with 4 mM K+. Reducing K+ from 4.0 mM to 2.5 or 1.0 mM depolarized HypoPP fibers but hyperpolarized normal fibers. Adding 12 mU/mL of insulin to bathing fluids increased the depolarization of HypoPP fibers and increased the hyperpolarization of normal fibers. Depolarized HypoPP had increased 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 or by insulin. Insulin reduced the conductance of the inward rectifier K+ channel for outward-flowing currents. CONCLUSIONS: Insulin potentiates depolarization of hypokalemic periodic paralysis (HypoPP) fibers by reducing inward rectifier K+ conductance. The Ca2+ mutations in HypoPP indirectly derange membrane excitability by altering the function of other membrane channels.
OBJECTIVE: To define how insulin acts in hypokalemic periodic paralysis (HypoPP). BACKGROUND: HypoPP results from point mutations of the skeletal muscle L-type Ca2+ channel. Attacks of flaccid paralysis are associated with hypokalemia and triggered by insulin. A persistent inward current causes depolarization-induced paralysis. The relationships of the Ca2+ channel mutations to the persistent inward current and how insulin triggers paralytic attacks are not yet known. METHODS: Intercostal muscle fibers from HypoPP and normal subjects were studied in vitro at 37 degrees C using two electrodes to determine action potential thresholds and a three-electrode voltage clamp to study membrane currents. RESULTS: HypoPP fibers were depolarized in bathing solution with 4 mM K+. Reducing K+ from 4.0 mM to 2.5 or 1.0 mM depolarized HypoPP fibers but hyperpolarized normal fibers. Adding 12 mU/mL of insulin to bathing fluids increased the depolarization of HypoPP fibers and increased the hyperpolarization of normal fibers. Depolarized HypoPP had increased 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 or by insulin. Insulin reduced the conductance of the inward rectifier K+ channel for outward-flowing currents. CONCLUSIONS:Insulin potentiates depolarization of hypokalemic periodic paralysis (HypoPP) fibers by reducing inward rectifier K+ conductance. The Ca2+ mutations in HypoPP indirectly derange membrane excitability by altering the function of other membrane channels.