Gating Pore Currents from S4 Mutations of NaV1.4: A Common Pathomechanism in Hypokalemic Periodic Paralysis

Abstract

The mechanism whereby missense mutations in charged residues of the S4 segments of CaV1.1 and NaV1.4 cause the skeletal muscle disorder hypokalemic periodic paralysis (HypoPP) remains poorly understood. Recent work suggests a possible common functional defect, in which HypoPP mutations produce aberrant ionic conductances flowing through the aqueous gating-pore in which the mutant S4 segment resides. We observed low-amplitude gating-pore currents for HypoPP mutations in the R1 and R2 positions of S4 in domain II in NaV1.4. Several features of these HypoPP-associated gating pore conductances were unexpected, and may provide insight into S4 segment function. For instance, gating pores exposed by mutations at the R2 site exhibited marked current saturation at hyperpolarized voltages. Saturation can be accounted for by a model with a single cation binding site very near the external surface of the electrical field. The ionic selectivity of different HypoPP gating pores is dependent on the substituted residue: histidine substitutions causing proton-selectivity, whereas other substitutions result in limited selectivity among monovalent cations. The pathophysiological significance of this dichotomy remains unclear. In addition, the low amplitude of the disease-associated gating pore currents (∼.1% of the peak Na current through the central pore) is probably insufficient to directly cause the large depolarization of affected muscle fibers during a paralytic attack. These small currents might predispose to episodic paralysis by potentiating the normal sarcolemmal propensity to depolarize upon reduction of external K+. This paradoxical depolarization is a consequence of the K+ dependence for the inward rectifier K+ conductance, which causes Vrest to deviate from Nernstian behavior. Thus, muscle fibers with an inward gating-pore current may function normally at most times, but may be poised for massive depolarization in the setting of minor perturbations of extracellular [K+].