title: An arrhythmia susceptibility gene in Caenorhabditis elegans.
abstract: kcne are evolutionarily conserved genes that encode accessory subunits of voltage-gated K(+) (Kv) channels. Missense mutations in kcne1, kcne2, and kcne3 are linked to congenital and acquired channelopathies in Homo sapiens. Here we show an unique example of conservation of kcne activities at genetic, physiological, functional, and pathophysiological level in Caenorhabditis elegans. Thus, mps-4 is the homologue of kcne1 that operates in human heart and inner ear. Like its KCNE relatives, MPS-4 assembles with a Kv channel, EXP-2, to form a complex that controls pharyngeal muscle contractility. MPS-4 modulates EXP-2 function in a similar fashion as KCNE proteins endow human channels. When defective, MPS-4, can induce abnormal repolarization by mechanisms that resemble the way KCNE proteins are thought to provoke arrhythmia in human heart. Mutation of a conserved aspartate residue associated with human disease (MPS-4-D74N) alters the functional attributes of the C. elegans current. Taken together these data underscore a significant conservation of KCNE activities in different pumps. This implies that C. elegans can develop into a system to study the molecular and genetic basis of KCNE-mediated muscle contractility and disease states.
authors.affiliation: University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Physiology and Biophysics, Piscataway, New Jersey 08854, USA.
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Federico
authors.initials: F
authors.lastname: Sesti
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D009119:Muscle Contraction / Q000235:genetics*; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*
chemical_list: D024642:Potassium Channels, Voltage-Gated