Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Cav1.1 mutation

Abstract

We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). 23Na and 1H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Cav1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a −20 mV shift of the steady-state inactivation curve. Both changes may be at least partially explained by an outward omega (gating pore) current at positive potentials. Moreover, this outward omega current of 27.5 nS/nF may cause the reduction of the overshoot by 13 mV and slowing of the upstroke of action potentials by 36% that are associated with muscle hypoexcitability (permanent weakness and myopathic myopathy). In addition to the outward omega current, we identified an inward omega pore current of 95 nS/nF at negative membrane potentials after long depolarizing pulses that shifts the R1242G residue above the omega pore constriction. A simulation reveals that the inward current might depolarize the fibre sufficiently to trigger calcium release in the absence of an action potential and therefore cause an electrically silent depolarization-induced muscle contracture. Additionally, evidence of the inward current can be found in 23Na magnetic resonance imaging-detected sodium accumulation and 1H magnetic resonance imaging-detected oedema. We hypothesize that the episodes are normokalaemic because of depolarization-induced compensatory outward potassium flux through both delayed rectifiers and omega pore. We conclude that the position of the R1242G residue before elicitation of the omega current is decisive for its conductance: if the residue is located below the gating pore as in the resting state then outward currents are observed; if the residue is above the gating pore because of depolarization, as in the inactivated state, then inward currents are observed. This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Cav1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis.

Domain III S4 in closed-state fast inactivation: Insights from a periodic paralysis mutation

“…6,7 Voltage sensor mutations at R3 that produce a depolarization-activated omega current were first identified for normokalemic periodic paralysis mutations in domain II of the sodium channel Na V 1.4 8 and domain IV of the calcium channel Ca V 1.1. 9 Recently, an R3 histidine mutation in domain IIIS4 of Na V 1.4 in hypokalemic periodic paralysis was described. 10 We characterized this (R1135H) and a novel cysteine mutation (R1135C) using heterologous expression in mammalian cells to study gating properties, and in Xenopus oocytes to study omega currents.…”

Gating pore currents, a new pathological mechanism underlying cardiac arrhythmias associated with dilated cardiomyopathy

“…5,6,[21][22][23] After long depolarization periods, the S4 segment of VSD should be naturally immobilized, resulting in a delay in the deactivation of the S4 segment. 24 While the molecular determinants of this process remain unclear, several hypotheses have been proposed, including the impact of a pore inactivation and the arrival of the S4 segment in a relaxed state.…”

“…In addition to being permeable at depolarized voltages, depolarization-activated gating pores are also temporarily permeable at hyperpolarized potentials due to the immobilization process. 5,6,[21][22][23]30 This results in a cation leak that is mainly enabled by the passage of Na C ions and that can last several tens of milliseconds. It is also interesting to note that very little is known about the kinetics of the deactivation of mutant S4 segments.…”

“…30 Hypokalemic periodic paralysis (HypoPP) is usually associated with the appearance of a hyperpolarization-activated gating pore, while normokalemic periodic paralysis (NormoPP) is usually associated with a depolarization-activated gating pore. 21,23,[31][32][33][34] Nevertheless, the association between a hyperpolarizationactivated or depolarization-activated gating pore and a specific clinical phenotype may not be as simple as associating hyperpolarization with HypoPP and depolarization with NormoPP. For example, the recently characterized R1128H/C mutation on Na v 1.4 creates a depolarizationactivated gating pore while the clinical phenotype is HypoPP.…”

“…6,13 The pathological mechanism underlying depolarization-activated gating pores has been hypothetically associated with a Na C leak at hyperpolarized potentials due to the temporary immobilization of the S4 segment. 6,21,22 It is important to note that the exact downstream consequences of a leak mainly enabled by K C during the AP remain unknown. To date, only one gain of function mutation on an ATP-activated K C channel has been identified and associated with the development of a DCM phenotype.…”