The sodium leak channel, NALCN, in health and disease

Abstract

Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs). There is growing evidence that the NALCN channelosome critically regulates its ion conduction. Both in mammals and invertebrates, animal models revealed an involvement in many processes such as locomotor behaviors, sensitivity to volatile anesthetics, and respiratory rhythms. There is also evidence that alteration in this NALCN channelosome can cause a wide variety of diseases. Indeed, mutations in the NALCN gene were identified in Infantile Neuroaxonal Dystrophy (INAD) patients, as well as in patients with an Autosomal Recessive Syndrome with severe hypotonia, speech impairment, and cognitive delay. Deletions in NALCN gene were also reported in diseases such as 13q syndrome. In addition, genes encoding NALCN, NLF- 1, UNC-79, and UNC-80 proteins may be susceptibility loci for several diseases including bipolar disorder, schizophrenia, Alzheimer's disease, autism, epilepsy, alcoholism, cardiac diseases and cancer. Although the physiological role of the NALCN channelosome is poorly understood, its involvement in human diseases should foster interest for drug development in the near future. Toward this goal, we review here the current knowledge on the NALCN channelosome in physiology and diseases.

Keywords: NALCN; UNC-79; UNC-80; excitability; ion channel.

Figure 1

Predicted molecular make-up of NALCN. The predicted structure of NALCN is similar to α/α₁ subunits of voltage-gated Na⁺ and Ca²⁺ channels (Lee et al., 1999). (A) It has four homologs repeats (domains I–IV) each composed of six transmembrane segments (S1–6). Four pore-forming loops (P-loops) spanning from S5 to S6 make up the ion selectivity filter. The intracellular loop linking domains I and II of NALCN interacts with M3R and molecular determinants involved in the regulation by CaSR are located in the carboxy-terminus (Swayne et al., ; Lu et al., 2010). The S5/P loop/S6 segment of transmembrane domain II is required for the interaction with NLF-1 (Xie et al., 2013). (B) Alternative events (shown in green) are detected in the intracellular loop linking domains II and III, in the P-loops of domains II and III, as well as in the carboxy-terminus (Senatore et al., ; data not shown). Mutations found in patients with INAD and an autosomal recessive syndrome with severe hypotonia, speech impairment, and cognitive delay are shown (Al-Sayed et al., ; Koroglu et al., 2013).

Figure 2

Schematic representation of the NALCN channelosome. The NALCN ion channel interacts with the M3 muscarinic receptor (M3R) that activates the channel through a G protein-independent and Src Family of Tyrosine Kinases (SFK)-dependent pathway upon activation by acetylcholine (Swayne et al., 2009). UNC-80 interacts with NALCN and SFKs and acts as a scaffolding protein (Wang and Ren, ; Lu et al., 2010). In addition, UNC-80 is involved in the expression levels of NALCN and UNC-79 as well as their neuronal localization (Jospin et al., ; Yeh et al., 2008). UNC-79 interacts with UNC-80 but not NALCN and is involved in the expression levels and the neuronal localization of NALCN and UNC-80 (Yeh et al., 2008). CaSR was found to regulate NALCN channel activity by an uncharacterized mechanism involving G-proteins activation and UNC-80 (Lu et al., 2010). For clarity, NLF-1, an endoplasmic reticulum-resident protein that interacts with NALCN and is possibly involved in its folding is shown apart. It is not known whether the interactions mentioned above are direct or not.