Stephen C.Cannon, Dept of Neurology, 5323 Harry Hines Blvd., UT Southwestern Medical Center, Dallas, TX 75390steve.cannon@utsouthwestern.edu
Submitted July 22, 2009
I thank Dr. Ruff for his comments. While the enhanced Na+ channel inactivation for HypoPP Type 2 mutations may contribute to the reduced Na+ current, and therefore a more sluggish rising phase of the action potential, the fact that this effect was not reversed by artificial hyperpolarization argues that another factor must be at work. [9]
Using Na+ MR spectroscopy, Jurkott-Rott et al. have recently shown an elevation of myoplasmic Na content interictally for HypoPP patients with Na or Ca channel mutations. [8] Moreover, the Na overload was exacerbated by limb cooling to induce weakness. The reduced Na+ gradient in this situation is predicted to shift the Nernst potential by 15 mV, which in turn would decrease the Na+ current by about 20% over the voltage range from -30 to -10 mV.
For the Kir conductance, the ictal shift of K+ from the interstitial space to the myoplasm would increase the gradient and therefore at first glance would increase the K+ current that maintains Vrest. However, this effect is overwhelmed by the hyperpolarized shift of the rectification point for the Kir conductance in low external K+, with the end result being a marked decrease in the “outward limb” of the Kir current at the normal value of Vrest.
This effective decrease in the outward Kir current and the presence of a small gating pore leak both contribute to the pathological depolarization of Vrest during an attack of HypoPP. [10]
References
9. Jurkat-Rott K, Mitrovic N, Hang C, et al. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci (US) 2000;97:9549-9554.
10. Struyk AF, Cannon SC. Paradoxical depolarization of Ba2+- treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 2008;37:326-337.
Disclosure: Dr. Cannon serves on the Scientific Advisory Committee for the Muscular Dystrophy Association.
I thank Dr. Ruff for his comments. While the enhanced Na+ channel inactivation for HypoPP Type 2 mutations may contribute to the reduced Na+ current, and therefore a more sluggish rising phase of the action potential, the fact that this effect was not reversed by artificial hyperpolarization argues that another factor must be at work. [9]
Using Na+ MR spectroscopy, Jurkott-Rott et al. have recently shown an elevation of myoplasmic Na content interictally for HypoPP patients with Na or Ca channel mutations. [8] Moreover, the Na overload was exacerbated by limb cooling to induce weakness. The reduced Na+ gradient in this situation is predicted to shift the Nernst potential by 15 mV, which in turn would decrease the Na+ current by about 20% over the voltage range from -30 to -10 mV.
For the Kir conductance, the ictal shift of K+ from the interstitial space to the myoplasm would increase the gradient and therefore at first glance would increase the K+ current that maintains Vrest. However, this effect is overwhelmed by the hyperpolarized shift of the rectification point for the Kir conductance in low external K+, with the end result being a marked decrease in the “outward limb” of the Kir current at the normal value of Vrest.
This effective decrease in the outward Kir current and the presence of a small gating pore leak both contribute to the pathological depolarization of Vrest during an attack of HypoPP. [10]
References
9. Jurkat-Rott K, Mitrovic N, Hang C, et al. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci (US) 2000;97:9549-9554.
10. Struyk AF, Cannon SC. Paradoxical depolarization of Ba2+- treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 2008;37:326-337.
Disclosure: Dr. Cannon serves on the Scientific Advisory Committee for the Muscular Dystrophy Association.