Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?

Abstract

Hypokalaemic periodic paralysis (hypoPP) is the archetypal skeletal muscle channelopathy caused by dysfunction of one of two sarcolemmal ion channels, either the sodium channel Nav1.4 or the calcium channel Cav1.1. Clinically, hypoPP is characterised by episodes of often severe flaccid muscle paralysis, in which the muscle fibre membrane becomes electrically inexcitable, and which may be precipitated by low serum potassium levels. Initial functional characterisation of hypoPP mutations failed to adequately explain the pathomechanism of the disease. Recently, as more pathogenic mutations involving loss of positive charge have been identified in the S4 segments of either channel, the hypothesis that an abnormal gating pore current may be important has emerged. Such an aberrant gating pore current has been identified in mutant Nav1.4 channels and has prompted potentially significant advances in this area. The carbonic anhydrase inhibitor acetazolamide has been used as a treatment for hypokalaemic periodic paralysis for over 40 years but its precise therapeutic mechanism of action is unclear. In this review we summarise the recent advances in the understanding of the molecular pathophysiology of hypoPP and consider how these may relate to the reported beneficial effects of acetazolamide. We also consider potential areas for future therapeutic development.

Figure 1

A, diagrammatic representation of Cav1.1 with voltage sensor mutations highlighted. B, diagrammatic representation of Nav1.4 with voltage sensor mutations highlighted. C, configuration of four domains in each channel to form a single ion-selective pore. *There is evidence that R675G has a gating pore opened by depolarisation. This is in contrast to the gating pore which is open at hyperpolarising potentials for the other SCN4A mutants studied to date. The phenotype of the R675G/Q/W mutants also differs being one of potassium-sensitive normokalaemic periodic paralysis.

Figure 2

An aberrant current permeable to protons could stimulate the NHE and NBC transporters with a resultant increase in intracellular sodium ions. Stimulation of the monocarboxylate transporter would result in increased lactate efflux from the cell which has been proposed as contributory to vacuolar formation (see text). MCT, monocarboxylate transporter; NHE, sodium–hydrogen anti-port exchanger; NBC, sodium-dependent bicarbonate transporter; CA, carbonic anhydrase.

Figure 3

Acetazolamide (ACZ) inhibits the carbonic anhydrase (CA) present in the tubular lumen preventing the conversion of H₂CO₃ to CO₂ and H₂O. H₂CO₃ dissociates to H⁺ and HCO₃⁻. Bicarbonate is lost in the tubular lumen producing a metabolic acidosis. Within the proximal tubular cell itself ACZ blocks CA preventing the conversion of CO₂ and H₂O to H⁺ and HCO₃⁻. The reduction in protons reduces the re-absorption of sodium ions which are excreted in the urine.