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

Abstract

PurposeFamilial 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.MethodsWe 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.ResultsPatient 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.ConclusionThese 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.

Atypical periodic paralysis and myalgia

“…On the basis of the recent observation of altered BK channel activity in RYR1-mutated smooth muscle cells, 10 one possibility is via an impairment of BK channel–mediated membrane repolarization due to altered intracellular calcium homeostasis, but this requires further study. 10 , 21 , 22 …”

Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: pharmacological perspectives

“…The abnormal activation of BK channel observed during hyperkalemia is consistent with biophysical property of the channel whose single channel conductance is enhanced in response to elevated external K ϩ ion concentration. BK channel protein levels were significantly lower in the membrane fraction and higher in the cytosolic fraction of hypokalemic periodic paralysis (hypoPP) patient muscle cells than normal cells, even after cell depolarization suggesting an the altered subcellular distribution of BK channels in this disorder (46).…”

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review

“…BK channels appear to actively participate in fibre transition in a cell-line-based and in a rat ischemia–reperfusion model of hyperkalaemia [ 198 , 199 ]. In hypokalaemia periodic paralysis (hypoPP) patients, BK channel expression in the membrane fraction of muscle cells was detected in significantly lower amounts compared to the cytosolic compartment, emphasising the role of channel redistribution in pathological states [ 200 ]. BK channel activators (e.g., acetazolamide, dichlorphenamide) administered together with Na + channel inhibitors may alleviate the weakness and myotonia in patients [ 201 ].…”