Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium. H., Wulf, M., Weidling, C., Rasmussen, L. Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. Nalcn is a “leak” sodium channel that regulates excitability of brainstem chemosensory neurons and breathing. The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons. A conserved bicycle model for circadian clock control of membrane excitability. NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion. UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. The ion channel narrow abdomen is critical for neural output of the Drosophila circadian pacemaker. Our results provide a structural blueprint to understand the physiology of the NALCN channelosome and a template for drug discovery to modulate the resting membrane potential. Key constraints between the UNC79–UNC80 subcomplex and the NALCN DI–DII and DII–DIII linkers were identified, leading to a model of channelosome gating. Single-channel analyses uncovered a low open probability for the wild-type complex, highlighting the tightly closed S6 gate in the structure, and providing a basis to interpret the altered gating properties of disease-causing variants. Calmodulin copurifies bound to the carboxy-terminal domain of NALCN, identifying this region as a putative modulatory hub. UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly, which docks intracellularly onto the NALCN–FAM155A pore-forming subcomplex. Here we determined the structure of the NALCN channelosome, an approximately 1-MDa complex, as fundamental aspects about the composition, assembly and gating of this channelosome remain obscure. NALCN, UNC79 and UNC80 are essential in rodents 2, 9, 13, and mutations in human NALCN and UNC80 cause severe developmental and neurological disease 14, 15. NALCN requires FAM155A, UNC79 and UNC80 to function, but the role of these auxiliary subunits is not understood 3, 7, 9, 10, 11, 12. Depolarizing sodium (Na +) leak currents carried by the NALCN channel regulate the resting membrane potential of many neurons to modulate respiration, circadian rhythm, locomotion and pain sensitivity 1, 2, 3, 4, 5, 6, 7, 8.
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