The sodium leak channel, non selective (NC-IUPHAR tentatively recommends the nomenclature Na_Vi2.1, W.A. Catterall, personal communication) is structurally a member of the family of voltage-gated sodium channel family (Na_v1.1-Na_v1.9) [1,9]. In contrast to the latter, Na_Vi2.1, is voltage-insensitive (denoted in the subscript 'vi' in the tentative nomenclature) and possesses distinctive ion selectivity and pharmacological properties. Na_Vi2.1, which is insensitive to tetrodotoxin (10 µM), has been proposed to mediate the tetrodotoxin-resistant and voltage-insensitive Na⁺ leak current (I_L-Na) observed in many types of neurone [2]. However, whether Na_Vi2.1 is constitutively active has been challenged [7]. Na_Vi2.1 is widely distributed within the central nervous system and is also expressed in the heart and pancreas specifically, in rodents, within the islets of Langerhans [1-2]. Recently, Na_Vi2.1 has been proposed to be a core effector for the action of inhibitory G proteins [5].

In native and recombinant expression systems Na_Vi2.1 can be activated by stimulation of NK₁ (in hippocampal neurones), neurotensin (in ventral tegmental area neurones) and M3 muscarinic acetylcholine receptors (in MIN6 pancreatic β-cells) and in a manner that is independent of signalling through G proteins [3,7]. Pharmacological and molecular biological evidence indicates such modulation to occur though a pathway that involves the activation of Src family tyrosine kinases. It is suggested that Na_Vi2.1 exists as a macromolecular complex with M3 receptors [7] and peptide receptors [3], in the latter instance in association with the protein UNC-80, which recruits Src to the channel complex [3,8]. By contrast, stimulation of Na_vi2.1 by decreased extracellular Ca²⁺ concentration is G protein dependent and involves a Ca²⁺-sensing G protein-coupled receptor and UNC80 which links Na_vi2.1 to the protein UNC79 in the same complex [4]. Na_vi2.1 null mutant mice have severe disturbances in respiratory rhythm and die within 24 hours of birth [2]. Na_vi2.1 heterozygous knockout mice display increased serum sodium concentrations in comparison to wildtype littermates and a role for the channel in osmoregulation has been postulated [6].

* Key recommended reading is highlighted with an asterisk

* Cochet-Bissuel M, Lory P, Monteil A. (2014) The sodium leak channel, NALCN, in health and disease. Front Cell Neurosci, 8: 132. [PMID:24904279]

Gilon P, Rorsman P. (2009) NALCN: a regulated leak channel. EMBO Rep, 10 (9): 963-4. [PMID:19662077]

* Lu TZ, Feng ZP. (2012) NALCN: a regulator of pacemaker activity. Mol Neurobiol, 45 (3): 415-23. [PMID:22476981]

* Philippart F, Khaliq ZM. (2018) G_i/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. Elife, 7. DOI: 10.7554/eLife.40984 [PMID:30556810]

Swayne LA, Mezghrani A, Lory P, Nargeot J, Monteil A. (2010) The NALCN ion channel is a new actor in pancreatic β-cell physiology. Islets, 2 (1): 54-6. [PMID:21099296]

* Waxman SG, Zamponi GW. (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci, 17 (2): 153-63. [PMID:24473263]

1. Lee JH, Cribbs LL, Perez-Reyes E. (1999) Cloning of a novel four repeat protein related to voltage-gated sodium and calcium channels. FEBS Lett, 445 (2-3): 231-6. [PMID:10094463]

2. Lu B, Su Y, Das S, Liu J, Xia J, Ren D. (2007) The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell, 129 (2): 371-83. [PMID:17448995]

3. Lu B, Su Y, Das S, Wang H, Wang Y, Liu J, Ren D. (2009) Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature, 457 (7230): 741-4. [PMID:19092807]

4. Lu B, Zhang Q, Wang H, Wang Y, Nakayama M, Ren D. (2010) Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron, 68 (3): 488-99. [PMID:21040849]

5. Philippart F, Khaliq ZM. (2018) G_i/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. Elife, 7. DOI: 10.7554/eLife.40984 [PMID:30556810]

6. Sinke AP, Caputo C, Tsaih SW, Yuan R, Ren D, Deen PM, Korstanje R. (2011) Genetic analysis of mouse strains with variable serum sodium concentrations identifies the Nalcn sodium channel as a novel player in osmoregulation. Physiol Genomics, 43 (5): 265-70. [PMID:21177381]

7. Swayne LA, Mezghrani A, Varrault A, Chemin J, Bertrand G, Dalle S, Bourinet E, Lory P, Miller RJ, Nargeot J et al.. (2009) The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic beta-cell line. EMBO Rep, 10 (8): 873-80. [PMID:19575010]

8. Wang H, Ren D. (2009) UNC80 functions as a scaffold for Src kinases in NALCN channel function. Channels (Austin), 3 (3): 161-3. [PMID:19535918]

9. Yu FH, Catterall WA. (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE, 2004 (253): re15. [PMID:15467096]