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., 2009; 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., 2013; 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., 2013; Koroglu et al., 2013).