scholarly journals Na leak with gating pore properties in hypokalemic periodic paralysis V876E mutant muscle Ca channel

2017 ◽  
Vol 149 (12) ◽  
pp. 1139-1148 ◽  
Author(s):  
Clarisse Fuster ◽  
Jimmy Perrot ◽  
Christine Berthier ◽  
Vincent Jacquemond ◽  
Pierre Charnet ◽  
...  

Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K+. The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the α1 subunit of the skeletal muscle voltage-gated Ca2+ channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current. Here we successfully transfer cDNAs encoding GFP-tagged human wild-type (WT) and V876E HypoPP1 mutant α1 subunits into mouse muscles by electroporation. The expression profile of these WT and V876E channels shows a regular striated pattern, indicative of their localization in the t-tubule membrane. In addition, L-type Ca2+ current properties are the same in V876E and WT fibers. However, in the presence of an external solution containing low-Cl− and lacking Na+ and K+, V876E fibers display an elevated leak current at negative voltages that is increased by external acidification to a higher extent in V876E fibers, suggesting that the leak current is carried by H+ ions. However, in the presence of Tyrode’s solution, the rate of change in intracellular pH produced by external acidification was not significantly different in V876E and WT fibers. Simultaneous measurement of intracellular Na+ and current in response to Na+ readmission in the external solution reveals a rate of Na+ influx associated with an inward current, which are both significantly larger in V876E fibers. These data suggest that the V876E mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions that are likely responsible for the severe HypoPP1 symptoms associated with this mutation.

2017 ◽  
Vol 149 (12) ◽  
pp. 1061-1064 ◽  
Author(s):  
Stephen C. Cannon

Cannon reviews new evidence supporting a key role for anomalous inward currents in the etiology of hypokalemic periodic paralysis.


Author(s):  
T. Shimizu ◽  
Y. Muranaka ◽  
I. Ohta ◽  
N. Honda

There have been many reports on ultrastructural alterations in muscles of hypokalemic periodic paralysis (hpp) and hypokalemic myopathy(hm). It is stressed in those reports that tubular structures such as tubular aggregates are usually to be found in hpp as a characteristic feature, but not in hm. We analyzed the histological differences between hpp and hm, comparing their clinical manifestations and morphologic changes in muscles. Materials analyzed were biopsied muscles from 18 patients which showed muscular symptoms due to hypokalemia. The muscle specimens were obtained by means of biopsy from quadriceps muscle and fixed with 2% glutaraldehyde (pH 7.4) and analyzed by ordinary method and modified Golgimethod. The ultrathin section were examined in JEOL 200CX transmission electron microscopy.Electron microscopic examinations disclosed dilated t-system and terminal cistern of sarcoplasmic reticulum (SR)(Fig 1), and an unique structure like “sixad” was occasionally observed in some specimens (Fig 2). Tubular aggregates (Fig 3) and honeycomb structure (Fig 4) were also common characteristic structures in all cases. These ultrastructural changes were common in both the hypokalemic periodic paralysis and the hypokalemic myopathy, regardless of the time of biopsy or the duration of hypokalemia suffered.


Author(s):  
Özgül Keskin ◽  
Hatice Türe ◽  
Özge Köner ◽  
Ferdi Menda ◽  
Bora Aykaç

Author(s):  
Ji Yeon Lee ◽  
Haifeng Zheng ◽  
Kenton M. Sanders ◽  
Sang Don Koh

We characterized the two types of voltage-dependent inward currents in murine antral SMC. The HVA and LVA inward currents were identified when cells were bathed in Ca2+-containing physiological salt solution. We examined whether the LVA inward current was due to: 1) T-type Ca2+ channels, 2) Ca2+-activated Cl- channels, 3) non-selective cation channels (NSCC) or 4) voltage-dependent K+ channels with internal Cs+-rich solution. Replacement of external Ca2+ (2 mM) with equimolar Ba2+ increased the amplitude of the HVA current but blocked the LVA current. Nicardipine blocked the HVA current, and in the presence of nicardipine, T-type Ca2+ blockers failed to block LVA. The Cl- channel antagonist had little effect on LVA. Cation-free external solution completely abolished both HVA and LVA. Addition of Ca2+ in cation-free solution restored only HVA currents. Addition of K+ (5 mM) to cation-free solution induced LVA current that reversed at -20 mV. These data suggest that LVA is not due to T-type Ca2+ channels, Ca2+-activated Cl- channels or NSCC. Antral SMC express A-type K+ currents (KA) and delayed rectifying K+ currents (KV) with dialysis of high K+ (140 mM) solution. When cells were exposed to high K+ external solution with dialysis of Cs+-rich solution in the presence of nicardipine, LVA was evoked and reversed at positive potentials. These HK-induced inward currents were blocked by K+ channel blockers, 4-aminopyridine and TEA. In conclusion, LVA inward currents can be generated by K+ influx via KA and KV channels in murine antral SMC when cells were dialyzed with Cs+-rich solution.


1996 ◽  
Vol 6 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Christie L.S. Grosson ◽  
Jesus Esteban ◽  
Diane McKenna-Yasek ◽  
James F. Gusella ◽  
Robert H. Brown

2011 ◽  
Vol 286 (31) ◽  
pp. 27425-27435 ◽  
Author(s):  
Chih-Jen Cheng ◽  
Shih-Hua Lin ◽  
Yi-Fen Lo ◽  
Sung-Sen Yang ◽  
Yu-Juei Hsu ◽  
...  

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