Ion channels are essential components for the activity of a living cell. They are integral membrane proteins that allow specific ions to pass through lipid membranes following a concentration gradient. Several types of ion channels have been described and have been classified depending on their gating properties, their ionic selectivity, and their sensitivity to toxins and pharmacological agents. They have been shown to be involved in many signalling and control processes in the cell as well as in pathologies. In addition, ion channels are viewed as the “next G protein-coupled receptors” in term of potential therapeutic targets. The aim of this proposal is to investigate the properties and the physiological roles of the NALCN cation channel with an emphasis on pancreatic ß-cells. Only few data are available on NALCN to date. Indeed only a dozen research articles are available in PubMed. However, puzzling available data suggest that NALCN is an important player of neuronal excitability and is involved in the sensitivity to volatile anesthetic agents and ethanol, in the regulation of circadian rhythms, locomotor behavious, respiratory rhythm, metabolism, ethanol consumption, and osmoregulation. In addition, genetic studies suggest that NALCN could be a susceptibility locus for bipolar disorder and schizophrenia. We have recently shown that, in addition to the brain, NALCN is also expressed in pancreas in human. This pancreatic expression is restricted to islets of Langerhans in rodents. By using RNA interference and overexpression approaches in the mouse insulin secreting-cell line MIN6, we identified NALCN as the molecular basis of a sodium current previously described in mouse primary beta-cells. This current is activated by acetylcholine through a G protein-independent, TTX-resistant, and atropine-sensitive pathway. In addition, we determined that M3 is the muscarinic receptor subtype (M3R) implicated in NALCN activation through a Src family of tyrosine kinases (SFKs)-dependent pathway. This activation requires the physical association of M3R and NALCN in the same complex. Considering the importance of the cholinergic control in the regulation of glucose-stimulated insulin secretion from pancreatic ß-cells, our published work suggests that NALCN could be an important player of this process. This raises the possibility that NALCN could be a major target to modulate insulin secretion in type-2 diabetes. In the present proposal, we will combine the skills of two complimentary research team in order (i) to investigate the involvement of NALCN in pancreatic ß-cell physiology both in vitro and in vivo, (ii) to determine the molecular basis of the NALCN-containing protein complexes in this cell type, and (iii) to study the biophysical and pharmacological properties of NALCN in recombinant system. Considering our published data as well as our preliminary results, we are convinced that this research program will highlight NALCN as an important player in the regulation of glucose-stimulated insulin secretion by pancreatic ß-cells.