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

Abstract

The V876E mutation in the muscle voltage-gated Ca2+ channel induces hypokalemic periodic paralysis. Fuster et al. show that the mutation generates strong resting inward leak Na+ currents even though it is not located in the voltage sensor segments.

When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis

“…The properties of the voltage‐gated Ca 2+ channel were found not to be changed in fibres transfected with the HypoPP1 V876E mutant‐GFP‐tagged Cav1.1 α1 subunits, demonstrating and confirming that the HypoPP1 pathogenesis is not related to any change in the Ca 2+ channel function of Cav1.1 (Fuster et al . ).…”

“…Indeed, mouse fibres expressing the HypoPP1 V876E mutant Cav1.1 α1 subunits were also found to exhibit an extra leak H + conductance in the absence of external Na + and K + ions that displayed an inward rectification for potentials lower than −50 to −40 mV (Fuster et al . ). However, in the presence of a physiological external solution, the proton influx at negative potentials reflected by the rate of intracellular acidification was not augmented in V876E fibres, indicating that the extra leak current carries monovalent cations other than protons.…”

“…at least 3 times larger than that measured for the R1239H mutation (Fuster et al . ). In agreement with this very large leak, the V876E mutation has been characterized by an uncommon early age of onset of the disease, high penetrance and a very severe prognosis (Ke et al .…”

“…The gating pore current was found to be carried by H + and Na + for the R1239H and the V876E HypoPP1 mutations, respectively (Fuster et al . , b).…”

“…In order to complement these data and circumvent possible adaptive compensatory mechanisms and/or ultrastructural abnormalities that may develop in these model systems, our group acutely expressed in adult mouse hindlimb muscles wild‐type (WT), HypoPP1 R1239H and V876E mutant‐GFP‐tagged Cav1.1 α1 subunits (Fuster et al . , b). Striated patterns of expression of WT, R1239H and V876E subunits gave evidence for their proper localization in the t‐tubule membrane.…”