Analysis of a unique cation channel (LNALCN) that can either be a calcium channel or a sodium channel

细胞的兴奋性取决于通过离子通道的离子流动的调节，例如通过钠离子或钙离子的阳离子通道。钠离子和钙离子在离子通道中服务的两个世界是不同的。钠是一种惰性电荷载体，可刺激细胞膜，如神经动作电位。细胞内钙离子瞬间增加，触发细胞内的信号传导。虽然细胞可以承受高钠离子浓度，但钙的静息浓度至少比钠离子低50,000倍。钙信号通过钙通道的排他性是离子通道孔中的对称过滤器，它提供了钙离子比钠离子10,000倍的选择性。钠离子通道具有不对称的孔过滤器，对竞争阳离子的歧视较小。我们发现，蜗牛NALCN通道的替代版本用一个看起来像钙通道孔的对称孔取代了不对称孔。我们报道了蜗牛NALCN形式的LNALCN-Ca具有对称孔，对钙离子具有高度选择性，而第二种形式的LNALCN-Na具有不对称孔，对钠离子具有高度选择性。在所有报道的基因组中，只有蜗牛NALCN含有两种形式的成孔外显子，这使得NALCN具有独特的渗透钙离子（LNALCN-Ca）或主要渗透钠离子（LNALCN-Na）的能力。NALCN是一种非常新颖的通道，在《细胞》杂志（2007）上首次报道为泄漏钠电导通道，并在2009年《自然》杂志上发表了一篇后续论文。我们将这种新的漏钠电导通道重新定义为电位钙通道。我们的离子通道报告可以通过选择性剪接改变其离子选择性，这是离子通道研究中最新颖的发现之一，其分析构成了NSERC发现基金的基础。

The excitability of a cell depends on the regulation of ion flow through ion channels, such as cation channels that pass sodium ions or calcium ions. The two worlds that sodium and calcium ions service in ion channels are different. Sodium is an inert charge carrier, that serves to excite cell membranes such as in nerve action potentials. Calcium ions increase transiently inside cells to trigger signaling in cells. While cells tolerate high sodium ion concentrations, resting concentrations of calcium is at least 50,000 times lower than sodium ions. The exclusivity of the calcium signal through calcium channels is a symmetrical filter in the ion channel pore that provides 10,000 fold selectivity of calcium ions over sodium ions. Sodium channels possess an asymmetrical pore filter that is less discriminatory against rival cations. We have found that alternative versions of the snail NALCN channel replaces the asymmetrical pore with a symmetrical pore that looks like a calcium channel pore. We report that the snail NALCN form LNALCN-Ca has a symmetrical pore that is highly selective for calcium ions and a second form, LNALCN-Na has an asymmetrical pore that is highly selective for sodium ions. Only the snail NALCN out of all reported genomes, contains two forms of a pore-forming exon, which engenders NALCN with a unique capacity to permeate either calcium ions (LNALCN-Ca) or mostly sodium ions (LNALCN-Na). NALCN is a highly novel channel, first reported as a leak sodium conductance channel in the Journal, Cell (2007) and in a follow up paper appeared in Nature in 2009. We redefine this novel leak sodium conductance channel as a potential calcium channel. Our report of an ion channel that can switch its ion selectivity through alternative splicing is one of the most novel findings in ion channel research, and its analyses forms the basis of this NSERC Discovery Grant.