NALCN: a regulated leak channel

The literature on ion channels is extensive; searching PubMed with the term ‘ion channel’ results in close to 120,000 hits. Few of us have the energy—let alone the time—to keep up. However, should you wish to know everything about one functionally important channel, then read on; here might be the channel just for you! The Na+ leak channel, non‐selective (NALCN) was first cloned in 1999 (Lee et al , 1999) but its true nature was not unveiled until 2007. To date, the entire literature on NALCN comprises fewer than ten papers, even when one considers its orthologues in Drosophila melanogaster and Caenorhabditis elegans .NALCN is a member of the 4 × 6TM family of ion channels, which comprise four homologous domains, each with six transmembrane (TM) segments. The family is encoded by 21 genes and includes voltage‐gated Na+‐selective and Ca2+‐selective ion channels (Lu et al , 2007) that have crucial roles in almost every excitable cell of the body. Nalcn encodes a protein that has fewer positive charges in the voltage‐sensing S4 segment than other members of the 4 × 6TM family and that is responsible for a voltage‐independent and tetrodotoxin (TTX)‐resistant non‐selective Na+ ‘leak’ current.The physiological significance of NALCN was highlighted by the finding that mice lacking the channel have abnormal respiratory rhythm and die within 24 h of birth. In addition, hippocampal neurons isolated from Nalcn knockout mice have reduced excitability. It seems that NALCN contributes to—but is almost certainly not the only channel responsible for—the elusive background leakage current often referred to as I L, which was first postulated by Hodgkin & Huxley (1952) but has been difficult to identify due to the lack of selective antagonists. A recent study revealed that …