Abstract
NALCN is a member of the family of ion channels with four homologous, repeat domains that include voltage-gated calcium and sodium channels. NALCN is a highly conserved gene from simple, extant multicellular organisms without nervous systems such as sponges and placozoans and mostly remains a single gene compared to the calcium and sodium channels which diversified into twenty genes in humans. The single NALCN gene has alternatively-spliced exons at exons 15 or exon 31 that splices in novel selectivity filter residues that resemble calcium channels (EEEE) or sodium channels (EKEE or EEKE). NALCN channels with alternative calcium, (EEEE) and sodium, (EKEE or EEKE) -selective pores are conserved in simple bilaterally symmetrical animals like flatworms to non-chordate deuterostomes. The single NALCN gene is limited as a sodium channel with a lysine (K)-containing pore in vertebrates, but originally NALCN was a calcium-like channel, and evolved to operate as both a calcium channel and sodium channel for different roles in many invertebrates. Expression patterns of NALCN-EKEE in pond snail, Lymnaea stagnalis suggest roles for NALCN in secretion, with an abundant expression in brain, and an up-regulation in secretory organs of sexually-mature adults such as albumen gland and prostate. NALCN-EEEE is equally abundant as NALCN-EKEE in snails, but is greater expressed in heart and other muscle tissue, and 50% less expressed in the brain than NALCN-EKEE. Transfected snail NALCN-EEEE and NALCN-EKEE channel isoforms express in HEK-293T cells. We were not able to distinguish potential NALCN currents from background, non-selective leak conductances in HEK293T cells. Native leak currents without expressing NALCN genes in HEK-293T cells are NMDG+ impermeant and blockable with 10 µM Gd3+ ions and are indistinguishable from the hallmark currents ascribed to mammalian NALCN currents expressed in vitro by Lu et al. in Cell. 2007 Apr 20;129(2):371-83.
Highlights
The first evidence for the existence of NALCN ion channels came from Drosophila geneticist Hermann Muller during his classical X-ray mutagenesis studies in the 1930s [1]
NALCN is an unusually conserved and short, 4-domain ion channel NALCN is slightly closer in sequence to a yeast calcium channel
NALCN has been described as a Na+ leak conductance channel which contributes to membrane excitability and rhythmic behaviors [2,4,9,11]
Summary
The first evidence for the existence of NALCN ion channels came from Drosophila geneticist Hermann Muller during his classical X-ray mutagenesis studies in the 1930s [1]. NALCN is a single-copy gene crucial for survival in mammals, where gene knockdown is lethal in mice within 24 hours after birth due to severely disrupted respiratory rhythms [4]. Hippocampal neurons have resting membrane potentials ,10 mV more hyperpolarized in NALCN2/2 mice [4], and the channel is considered to provide a resting Na+ conductance in wild type neurons, not just in mammals [4] and in nematodes (C. elegans) [7,8,9], fruit fly (Drosophila) [2,10] and snail (Lymnaea) [11]. Analyses of mutant invertebrates suggest that NALCN is linked to anesthetic sensitivity [12], locomotion [13], diurnal rhythms [2,10], gap junction activity [7] and synaptic vesicle turnover [8]. NALCN expresses in a brain complex which includes accessory proteins UNC-79 and UNC-80 [15,16]
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