Patch clamp studies of the thr1313met mutant sodium channel causing paramyotonia congenita.
Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degrees C. At 27 degrees C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of -40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22 degrees C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, tau(h), for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at -60, -40, and -20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior.
Boulos
P T
PT
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Heiman-Patterson
T D
TD
Alexander
G M
GM
Tahmoush
A J
AJ
D000328:Adult; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008715:Methionine / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology; D020967:Myotonic Disorders / Q000235:genetics* / Q000503:physiopathology*; D009679:Nuclear Family; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013912:Threonine / Q000235:genetics
D015222:Sodium Channels; D013912:Threonine; D008715:Methionine