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Molecular cloning and genetic characterization of the mammalian and nematode nca gene family of four domain-type voltage-gated ion channels Hamming, Kevin Scott Christopher

Abstract

Voltage-gated ion channels (VGICs) are involved in numerous physiological processes including cellular excitability, electrical signaling and neurotransmitter release. VGICs have also been implicated in human diseases such as night blindness, migraine headaches, cardiovascular disease and certain movement and muscle disorders. While significant work has been performed towards identifying the different types of VGICs in native cells and their molecular counterparts, there still are a number of native conductances that remain to be fully characterized. The role that these "new" channels may play in normal physiological processes and disease states is not known. Thus, a complete study of these new channels is necessary to understand their basic properties and contributions to neuronal physiology. The goals of this study were to identify novel four domain-type VGICs and determine their physiological functions in mammalian and nematode model systems. Screening of the C. elegans genome and GenBank EST databases identified the nca family of four domain-type VGICs. Sequence comparisons between representative Ca2 + and Na+ channel α(i) subunits and that of the NCA channels revealed that the NCA channels form their own distinct family of VGICs based upon amino acid identity. Furthermore, these comparisons predict that the NCA channels may have unique ion selectivity, activation and inactivation properties. Despite repeated attempts under a variety of assay conditions, no functional currents were obtained for the full-length NCA channels transiently transfected into HEK tsA201 cells. The physiological functions of the nca-1 and nca-2 genes in C. elegans were examined using deletion mutant strains that contained predicted null mutations. The cellular expression patterns of nca-1 and nca-2 were determined using promoter

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