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
.