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.

The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion

“…Mutations in human NALCN have been associated with a spectrum of physiological impairments, including severe hypotonia, speech impairment, growth failure and cognitive delay 38,39 . The NALCN/NCA channel is a voltage-independent, Tetrodotoxin (TTX)-insensitive and substance P-potentiated constitutive Na þ -permeable channel 34,40 .…”

Blood pressure and risk of cancer progression – A possible connection with salt and voltage-gated sodium channel

“…invasiveness) [17]. We should note that two other types of sodium channel -epithelial sodium channel (ENaC) and sodium leak channel (NALCN) -are also expressed in cancer cells but their possible involvement in the cancer process is not as well understood [18,19]. Also, potassium can also contribute to blood pressure and a variety of potassium ion channels are also involved in the cancer process but this is outside the scope of the current hypothesis.…”

De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay

“…However, it remains unclear whether NALCN is actually an ion channel rather than a sensor of sodium. 16 In mammals, NALCN is most highly expressed in the central nervous system but is also found at moderate levels in the heart, lymph nodes, pancreas, and thyroid (summarized by Cochet-Bissuel et al 17 ). Unlike most known genes underlying DA syndromes, NALCN is not expressed in fetal skeletal muscle ( Figure S4).…”

“…23 In mice, NALCN has been shown to regulate respiration, 24 intestinal pacemaking activity in the interstitial cells of Cajal, 25 and serum sodium concentration. 26 Mutation of NALCN homologs in D. melanogaster, C. elegans, and L. stagnalis results in abnormal locomotion, 19,[27][28][29][30] disturbance of circadian rhythms, 29 disruption of normal respiratory rhythms, 31 and altered sensitivity to ethanol and some general anesthetics 30,32,33 (reviewed by Cochet-Bissuel et al 17 ). Homozygous Nalcn-null mice die shortly after birth and exhibit disrupted respiratory rhythm; mutant pups breath for 5 s, followed by 5 s of apnea.…”