Korean J Pediatr.  2014 Oct;57(10):445-450. 10.3345/kjp.2014.57.10.445.

The large-conductance calcium-activated potassium channel holds the key to the conundrum of familial hypokalemic periodic paralysis

• Kim JB
• Kim SJ
• Kang SY
• Yi JW
• Kim SM

• KMID: 2284384
• DOI: http://doi.org/10.3345/kjp.2014.57.10.445

Abstract

PURPOSE
Familial hypokalemic periodic paralysis (HOKPP) is an autosomal dominant channelopathy characterized by episodic attacks of muscle weakness and hypokalemia. Mutations in the calcium channel gene, CACNA1S, or the sodium channel gene, SCN4A, have been found to be responsible for HOKPP; however, the mechanism that causes hypokalemia remains to be determined. The aim of this study was to improve the understanding of this mechanism by investigating the expression of calcium-activated potassium (KCa) channel genes in HOKPP patients.
METHODS
We measured the intracellular calcium concentration with fura-2-acetoxymethyl ester in skeletal muscle cells of HOKPP patients and healthy individuals. We examined the mRNA and protein expression of KCa channel genes (KCNMA1, KCNN1, KCNN2, KCNN3, and KCNN4) in both cell types.
RESULTS
Patient cells exhibited higher cytosolic calcium levels than normal cells. Quantitative reverse transcription polymerase chain reaction analysis showed that the mRNA levels of the KCa channel genes did not significantly differ between patient and normal cells. However, western blot analysis showed that protein levels of the KCNMA1 gene, which encodes KCa1.1 channels (also called big potassium channels), were significantly lower in the membrane fraction and higher in the cytosolic fraction of patient cells than normal cells. When patient cells were exposed to 50 mM potassium buffer, which was used to induce depolarization, the altered subcellular distribution of BK channels remained unchanged.
CONCLUSION
These findings suggest a novel mechanism for the development of hypokalemia and paralysis in HOKPP and demonstrate a connection between disease-associated mutations in calcium/sodium channels and pathogenic changes in nonmutant potassium channels.

Keyword

Channelopathies; Hypokalemic periodic paralysis; Potassium channels

MeSH Terms

Blotting, Western
Calcium
Calcium Channels
Channelopathies
Cytosol
Humans
Hypokalemia
Hypokalemic Periodic Paralysis*
Large-Conductance Calcium-Activated Potassium Channels
Membranes
Muscle Weakness
Muscle, Skeletal
Paralysis
Polymerase Chain Reaction
Potassium
Potassium Channels
Potassium Channels, Calcium-Activated*
Reverse Transcription
RNA, Messenger
Sodium Channels
Calcium
Calcium Channels
Large-Conductance Calcium-Activated Potassium Channels
Potassium
Potassium Channels
Potassium Channels, Calcium-Activated
RNA, Messenger
Sodium Channels