Human ether-a-go-go (HERG) potassium channels play a critical role in cardiac repolarization and have been genetically linked to an inherited arrhythmia, the long QT syndrome.
unc-103 encodes the worm ortholog of HERG with 70 % amino acid identity in the conserved transmembrane and pore regions.
unc-103 gain-of-function (gf) mutants display a variety of phenotypes reflecting reduced muscle excitation. These phenotypes include defective egg-laying, paralysis and defects in defecation. Because the worm pharynx displays many similarities to the mammalian heart, we examined
unc-103 gf mutants for defects in pharyngeal pumping. We find that these mutants display lengthy pauses in pharyngeal pumping (as long as 7 seconds), reminiscent of cardiac bradydysrhythmias. Notably, in wildtype worms, HERG-specific blockers such as dofetilide and d-sotalol slow the rate of pharyngeal pumping, but do not induce pauses. Promoter-GFP fusion constructs reveal that
unc-103 is expressed in I1, I2 and NSM neurons, which innervate the pharynx. The molecular nature of the
unc-103 gf mutant is an A to T change at position 334 in the S6 domain, a region important for potassium channel gating. To understand the diverse effects of the
unc-103 gf mutation and HERG-specific blockers, we are undertaking an electrophysiological characterization of the wild type and UNC-103 gf mutant using a mammalian heterologous expression system. These studies may clarify whether complex ion channel gating effects underlie differences between the
unc-103 gf phenotype and the effects of HERG blockers in the pharynx. Furthermore, comparing the electrophysiological properties of wt UNC-103 with HERG in our expression system will also allow us to address structure/function differences using chimeric constructs of worm and human channels.