Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis
Robert L.Ruff, Cleveland VAMC/Case Western Reserve Univ., Neurology 127(W), CVAMC, 10701 East Blvd., Cleveland, OH 44106Robertlruff@aol.com
None
Submitted July 22, 2009
Matthews et al. highlight the importance of mutations in the arginine residues in S4 voltage sensors of skeletal muscle Ca2+ and Na+ channels in the genesis of hypokalemic periodic paralysis (HypoKPP) types 1 and 2. [1]
Previous studies have demonstrated that loss of charged arginine residues produces a leak current pathway through portions of the ion channel that support voltage-induced movements of the S4 segments. [2] Current flowing through the alternative ion pathway created by the S4 mutations could account for the anomalous cation depolarizing current that occurs in type 1 HypoKPP and is likely present in type 2 HypoKPP.
Current passage via an alternative pathway would also explain why the anomalous depoplarizing current is not blocked by traditional Na+ or Ca2+ channel blockers. [3] The highly selective association of the arginine gating pore mutations with the HypoKPP phenotype suggests that this type of mutation is likely key to the genesis of this phenotype.
The authors also consider whether other ion channel alterations associated with HypoKPP are important for creation of the phenotype. [1] Type 1 HypoKPP is associated with reduction in the outward current component of the inward rectifier K+ channel (Kir). [3] While reduced Kir may be an epiphenomena, a role for reduced Kir in the HypoKPP phenotype has been suggested. Reduced Kir is the ion channel defect responsible for Andersen syndrome, which includes a periodic paralysis phenotype. Increasing K+ current may be the mechanism of action of acetazolamide-induced improvement in HypoKPP symptoms. [4]
In type 2 HypoKPP, the Na+ channel mutations reduce the available Na+ current through enhanced channel inactivation. [5] The density of Na+ may be reduced in type 1 HypoKPP. [6] Lower Na+ current density is consistent with reduced action potential conduction velocity and could contribute to the HypoKPP phenotype by reducing membrane excitability thereby facilitating paralysis due to membrane inexcitabiity.
These arguments suggest the reduced Kir and Na+ currents contribute to the HypoKPP phenotype, yet they do not prove that they are critical. The arginine mutations directly produce the anomalous depolarizing current.
How do the mutations reduce other currents? Perhaps the mutations, by creating an alternative path for cations to enter, may indirectly contribute to the changes in Na+ and Kir channel function by altering the intracellular ionic composition. [6]
References
1. Matthews E, Labrum R, Sweeney MG, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009;72:1544-1547.
2. Struyk AF, Cannon SC. A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton selective gating pore. J Gen Physiol 2007;130:11-20.
3. Ruff RL. Insulin Acts in Hypokalemic Periodic Paralysis by Reducing Inward Rectifier K+ Current. Neurology 1999;53:1556-1563.
4. Tricarico D, Barbieri M, Camerino DC. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000;48:304-312.
5. Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalemic periodic paralysis type II. Brain 2002;125:835-843.
6. Ruff RL. Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis. Proc Natl Acad Sci (US) 2000;97:9832-9833.
Disclosures: Dr. Ruff was the Principal Investigator of Department of Veterans Affairs Merit Reviewed Research Program, “Human Skeletal Muscle Sodium Channels and Hypokalemic Periodic Paralysis.”
Matthews et al. highlight the importance of mutations in the arginine residues in S4 voltage sensors of skeletal muscle Ca2+ and Na+ channels in the genesis of hypokalemic periodic paralysis (HypoKPP) types 1 and 2. [1]
Previous studies have demonstrated that loss of charged arginine residues produces a leak current pathway through portions of the ion channel that support voltage-induced movements of the S4 segments. [2] Current flowing through the alternative ion pathway created by the S4 mutations could account for the anomalous cation depolarizing current that occurs in type 1 HypoKPP and is likely present in type 2 HypoKPP.
Current passage via an alternative pathway would also explain why the anomalous depoplarizing current is not blocked by traditional Na+ or Ca2+ channel blockers. [3] The highly selective association of the arginine gating pore mutations with the HypoKPP phenotype suggests that this type of mutation is likely key to the genesis of this phenotype.
The authors also consider whether other ion channel alterations associated with HypoKPP are important for creation of the phenotype. [1] Type 1 HypoKPP is associated with reduction in the outward current component of the inward rectifier K+ channel (Kir). [3] While reduced Kir may be an epiphenomena, a role for reduced Kir in the HypoKPP phenotype has been suggested. Reduced Kir is the ion channel defect responsible for Andersen syndrome, which includes a periodic paralysis phenotype. Increasing K+ current may be the mechanism of action of acetazolamide-induced improvement in HypoKPP symptoms. [4]
In type 2 HypoKPP, the Na+ channel mutations reduce the available Na+ current through enhanced channel inactivation. [5] The density of Na+ may be reduced in type 1 HypoKPP. [6] Lower Na+ current density is consistent with reduced action potential conduction velocity and could contribute to the HypoKPP phenotype by reducing membrane excitability thereby facilitating paralysis due to membrane inexcitabiity.
These arguments suggest the reduced Kir and Na+ currents contribute to the HypoKPP phenotype, yet they do not prove that they are critical. The arginine mutations directly produce the anomalous depolarizing current.
How do the mutations reduce other currents? Perhaps the mutations, by creating an alternative path for cations to enter, may indirectly contribute to the changes in Na+ and Kir channel function by altering the intracellular ionic composition. [6]
References
1. Matthews E, Labrum R, Sweeney MG, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009;72:1544-1547.
2. Struyk AF, Cannon SC. A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton selective gating pore. J Gen Physiol 2007;130:11-20.
3. Ruff RL. Insulin Acts in Hypokalemic Periodic Paralysis by Reducing Inward Rectifier K+ Current. Neurology 1999;53:1556-1563.
4. Tricarico D, Barbieri M, Camerino DC. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000;48:304-312.
5. Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalemic periodic paralysis type II. Brain 2002;125:835-843.
6. Ruff RL. Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis. Proc Natl Acad Sci (US) 2000;97:9832-9833.
Disclosures: Dr. Ruff was the Principal Investigator of Department of Veterans Affairs Merit Reviewed Research Program, “Human Skeletal Muscle Sodium Channels and Hypokalemic Periodic Paralysis.”