ID NALCN_HUMAN Reviewed; 1738 AA. AC Q8IZF0; Q6P2S6; Q6ZMI7; Q8IZZ1; Q8TAH1; DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 27-MAR-2024, entry version 185. DE RecName: Full=Sodium leak channel NALCN {ECO:0000305}; DE AltName: Full=CanIon; DE AltName: Full=Sodium leak channel non-selective protein; DE AltName: Full=Voltage gated channel-like protein 1; GN Name=NALCN {ECO:0000312|HGNC:HGNC:19082}; GN Synonyms=VGCNL1 {ECO:0000303|Ref.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Bonner T.I., Moses T., Detera-Wadleigh S.; RT "VGCNL1, a putative voltage-gated ion channel."; RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Bone, and Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-266. RX PubMed=12364586; DOI=10.1073/pnas.182412499; RA Chumakov I., Blumenfeld M., Guerassimenko O., Cavarec L., Palicio M., RA Abderrahim H., Bougueleret L., Barry C., Tanaka H., La Rosa P., Puech A., RA Tahri N., Cohen-Akenine A., Delabrosse S., Lissarrague S., Picard F.-P., RA Maurice K., Essioux L., Millasseau P., Grel P., Debailleul V., Simon A.-M., RA Caterina D., Dufaure I., Malekzadeh K., Belova M., Luan J.-J., Bouillot M., RA Sambucy J.-L., Primas G., Saumier M., Boubkiri N., Martin-Saumier S., RA Nasroune M., Peixoto H., Delaye A., Pinchot V., Bastucci M., Guillou S., RA Chevillon M., Sainz-Fuertes R., Meguenni S., Aurich-Costa J., Cherif D., RA Gimalac A., Van Duijn C., Gauvreau D., Ouellette G., Fortier I., RA Raelson J., Sherbatich T., Riazanskay N., Rogaev E., Raeymaekers P., RA Aerssens J., Konings F., Luyten W., Macciardi F., Sham P.C., Straub R.E., RA Weinberger D.R., Cohen N., Cohen D.; RT "Genetic and physiological data implicating the new human gene G72 and the RT gene for D-amino acid oxidase in schizophrenia."; RL Proc. Natl. Acad. Sci. U.S.A. 99:13675-13680(2002). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1428-1738. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP FUNCTION. RX PubMed=17448995; DOI=10.1016/j.cell.2007.02.041; RA Lu B., Su Y., Das S., Liu J., Xia J., Ren D.; RT "The neuronal channel NALCN contributes resting sodium permeability and is RT required for normal respiratory rhythm."; RL Cell 129:371-383(2007). RN [8] RP INVOLVEMENT IN IHPRF1. RX PubMed=23749988; DOI=10.1136/jmedgenet-2013-101634; RA Koeroglu C., Seven M., Tolun A.; RT "Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy RT with facial dysmorphism."; RL J. Med. Genet. 50:515-520(2013). RN [9] RP INVOLVEMENT IN CLIFAHDD, VARIANTS CLIFAHDD PRO-177; ILE-312; GLY-313; RP SER-509; SER-578; PHE-590; PRO-1165 AND MET-1446, AND CHARACTERIZATION OF RP VARIANTS CLIFAHDD SER-509 AND SER-578. RX PubMed=25683120; DOI=10.1016/j.ajhg.2015.01.003; RG University of Washington Center for Mendelian Genomics; RA Chong J.X., McMillin M.J., Shively K.M., Beck A.E., Marvin C.T., RA Armenteros J.R., Buckingham K.J., Nkinsi N.T., Boyle E.A., Berry M.N., RA Bocian M., Foulds N., Uzielli M.L., Haldeman-Englert C., Hennekam R.C., RA Kaplan P., Kline A.D., Mercer C.L., Nowaczyk M.J., RA Klein Wassink-Ruiter J.S., McPherson E.W., Moreno R.A., Scheuerle A.E., RA Shashi V., Stevens C.A., Carey J.C., Monteil A., Lory P., Tabor H.K., RA Smith J.D., Shendure J., Nickerson D.A., Bamshad M.J.; RT "De novo mutations in NALCN cause a syndrome characterized by congenital RT contractures of the limbs and face, hypotonia, and developmental delay."; RL Am. J. Hum. Genet. 96:462-473(2015). RN [10] RP CHARACTERIZATION OF VARIANTS CLIFAHDD SER-509 AND SER-578, CHARACTERIZATION RP OF VARIANT IHPRF1 LEU-1287, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=31409833; DOI=10.1038/s41598-019-48071-x; RA Bouasse M., Impheng H., Servant Z., Lory P., Monteil A.; RT "Functional expression of CLIFAHDD and IHPRF pathogenic variants of the RT NALCN channel in neuronal cells reveals both gain- and loss-of-function RT properties."; RL Sci. Rep. 9:11791-11791(2019). RN [11] RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND RP MUTAGENESIS OF ARG-146; ARG-152; ARG-155; GLU-280; ARG-481; ARG-484; RP LYS-487; GLU-554; ASP-558; ASP-561; ARG-989; ARG-992; ARG-995; LYS-1115; RP GLU-1119; ARG-1310; GLU-1389 AND ASP-1390. RX PubMed=32494638; DOI=10.1126/sciadv.aaz3154; RA Chua H.C., Wulf M., Weidling C., Rasmussen L.P., Pless S.A.; RT "The NALCN channel complex is voltage sensitive and directly modulated by RT extracellular calcium."; RL Sci. Adv. 6:eaaz3154-eaaz3154(2020). RN [12] {ECO:0007744|PDB:6XIW} RP STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) IN COMPLEX WITH NALF1, RP FUNCTION, CHARACTERIZATION OF VARIANTS CLIFAHDD PHE-590; GLN-1181 AND RP MET-1446, CHARACTERIZATION OF VARIANT IHPRF1 LEU-1287, DISULFIDE BOND, RP GLYCOSYLATION AT ASN-1064, SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=32698188; DOI=10.1038/s41586-020-2570-8; RA Kschonsak M., Chua H.C., Noland C.L., Weidling C., Clairfeuille T., RA Bahlke O.O., Ameen A.O., Li Z.R., Arthur C.P., Ciferri C., Pless S.A., RA Payandeh J.; RT "Structure of the human sodium leak channel NALCN."; RL Nature 587:313-318(2020). RN [13] {ECO:0007744|PDB:7CM3} RP STRUCTURE BY ELECTRON MICROSCOPY (3.10 ANGSTROMS) IN COMPLEX WITH NALF1, RP DISULFIDE BONDS, GLYCOSYLATION AT ASN-210; ASN-216 AND ASN-1064, FUNCTION, RP MUTAGENESIS OF PHE-325; ILE-328; PHE-332; LYS-504 AND LYS-505, AND ACTIVITY RP REGULATION. RX PubMed=33203861; DOI=10.1038/s41467-020-19667-z; RA Xie J., Ke M., Xu L., Lin S., Huang J., Zhang J., Yang F., Wu J., Yan Z.; RT "Structure of the human sodium leak channel NALCN in complex with RT FAM155A."; RL Nat. Commun. 11:5831-5831(2020). RN [14] RP VARIANT IHPRF1 LEU-1287. RX PubMed=24075186; DOI=10.1016/j.ajhg.2013.08.001; RA Al-Sayed M.D., Al-Zaidan H., Albakheet A., Hakami H., Kenana R., RA Al-Yafee Y., Al-Dosary M., Qari A., Al-Sheddi T., Al-Muheiza M., RA Al-Qubbaj W., Lakmache Y., Al-Hindi H., Ghaziuddin M., Colak D., Kaya N.; RT "Mutations in NALCN cause an autosomal-recessive syndrome with severe RT hypotonia, speech impairment, and cognitive delay."; RL Am. J. Hum. Genet. 93:721-726(2013). RN [15] RP VARIANT CLIFAHDD GLN-1181. RX PubMed=25864427; DOI=10.1002/humu.22797; RA Aoyagi K., Rossignol E., Hamdan F.F., Mulcahy B., Xie L., Nagamatsu S., RA Rouleau G.A., Zhen M., Michaud J.L.; RT "A gain-of-function mutation in NALCN in a child with intellectual RT disability, ataxia, and arthrogryposis."; RL Hum. Mutat. 36:753-757(2015). RN [16] RP VARIANTS VAL-312; PHE-1020 AND GLN-1181. RX PubMed=26763878; DOI=10.1038/jhg.2015.163; RA Fukai R., Saitsu H., Okamoto N., Sakai Y., Fattal-Valevski A., Masaaki S., RA Kitai Y., Torio M., Kojima-Ishii K., Ihara K., Chernuha V., Nakashima M., RA Miyatake S., Tanaka F., Miyake N., Matsumoto N.; RT "De novo missense mutations in NALCN cause developmental and intellectual RT impairment with hypotonia."; RL J. Hum. Genet. 61:451-455(2016). RN [17] RP VARIANTS CYS-317 AND PHE-595. RX PubMed=27214504; DOI=10.1055/s-0036-1584084; RA Karakaya M., Heller R., Kunde V., Zimmer K.P., Chao C.M., Nuernberg P., RA Cirak S.; RT "Novel mutations in the nonselective sodium leak channel (NALCN) lead to RT distal arthrogryposis with increased muscle tone."; RL Neuropediatrics 47:273-277(2016). CC -!- FUNCTION: Voltage-gated ion channel responsible for the resting Na(+) CC permeability that controls neuronal excitability (PubMed:17448995, CC PubMed:31409833). NALCN channel functions as a multi-protein complex, CC which consists at least of NALCN, NALF1, UNC79 and UNC80 CC (PubMed:32494638, PubMed:33203861). NALCN is the voltage-sensing, pore- CC forming subunit of the NALCN channel complex (PubMed:17448995). NALCN CC channel complex is constitutively active and conducts monovalent CC cations but is blocked by physiological concentrations of extracellular CC divalent cations (PubMed:32494638). In addition to its role in CC regulating neuronal excitability, is required for normal respiratory CC rhythm, systemic osmoregulation by controlling the serum sodium CC concentration and in the regulation of the intestinal pace-making CC activity in the interstitial cells of Cajal (By similarity). NALCN CC channel is also activated by neuropeptides such as neurotensin and CC substance P (SP) through a SRC family kinases-dependent pathway (By CC similarity). In addition, NALCN activity is enhanced/modulated by CC several GPCRs, such as CHRM3 (By similarity). CC {ECO:0000250|UniProtKB:Q8BXR5, ECO:0000269|PubMed:17448995, CC ECO:0000269|PubMed:31409833, ECO:0000269|PubMed:32494638, CC ECO:0000269|PubMed:33203861}. CC -!- ACTIVITY REGULATION: Inhibited by low micromolar concentrations of CC Gd(3+) and high micromolar concentrations of verapamil. Insensitive to CC tetrodotoxin (TTX) and potentiated by low external Ca(2+) CC concentration. {ECO:0000269|PubMed:32494638, CC ECO:0000269|PubMed:33203861}. CC -!- SUBUNIT: Found in a complex with NALCN, UNC79, UNC80 and NACL1; these CC auxiliary subunits are indispensable for the function of NALCN channel CC (PubMed:32494638, PubMed:32698188, PubMed:33203861). Interacts with CC UNC80; required for the NALCN activation/inhibition by GPCRs in CC neurons. Found in a complex with NALCN, UNC79 and UNC80; UNC80 bridges CC NALCN to UNC79 (By similarity). Interacts with CHRM3 (By similarity). CC {ECO:0000250|UniProtKB:Q8BXR5, ECO:0000269|PubMed:32494638, CC ECO:0000269|PubMed:32698188, ECO:0000269|PubMed:33203861}. CC -!- INTERACTION: CC Q8IZF0; P20309: CHRM3; NbExp=3; IntAct=EBI-7085333, EBI-2687785; CC Q8IZF0; P50222: MEOX2; NbExp=3; IntAct=EBI-7085333, EBI-748397; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31409833, CC ECO:0000269|PubMed:32494638, ECO:0000269|PubMed:32698188}; Multi-pass CC membrane protein {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8IZF0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IZF0-2; Sequence=VSP_030190, VSP_030191; CC Name=3; CC IsoId=Q8IZF0-3; Sequence=VSP_030188, VSP_030189; CC -!- DOMAIN: Contains 24 transmembrane helices (TM) that form four CC homologous functional repeats connected by intracellular linkers. Each CC of the four internal repeats contains five hydrophobic transmembrane CC segments (S1, S2, S3, S5, S6) and one positively charged transmembrane CC segment (S4). S4 segments represent the voltage-sensor. S4 CC transmembrane segments lack some of the charged residues (K and R) CC found at every third position in the S4s of the NaV, CaV, and KV CC channels. Pore-forming loops (P loops) between S5 and S6 of each domain CC form an EEKE sodium- ion selectivity filter a mixture between the EEEE CC found in the CaVs and the DEKA of NaVs. Voltage-sensing domains (VSDs), CC formed by S1 to S4 of each domain, detect changes in membrane potential CC and induce the opening or closing of the ion-conducting pore domain, CC formed by S5 and S6. {ECO:0000250|UniProtKB:Q8BXR5}. CC -!- PTM: Phosphorylated on tyrosine residues. CC {ECO:0000250|UniProtKB:Q8BXR5}. CC -!- DISEASE: Hypotonia, infantile, with psychomotor retardation and CC characteristic facies 1 (IHPRF1) [MIM:615419]: A neurodegenerative CC disease characterized by variable degrees of hypotonia, speech CC impairment, intellectual disability, pyramidal signs, subtle facial CC dysmorphism, and chronic constipation. Some patients manifest CC neuroaxonal dystrophy, optic atrophy, unmyelinated axons and spheroid CC bodies in tissue biopsies. {ECO:0000269|PubMed:23749988, CC ECO:0000269|PubMed:24075186, ECO:0000269|PubMed:31409833, CC ECO:0000269|PubMed:32698188}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Congenital contractures of the limbs and face, hypotonia, and CC developmental delay (CLIFAHDD) [MIM:616266]: A disease characterized by CC congenital contractures of the limbs and face, resulting in CC characteristic facial features, abnormal tone, most commonly manifested CC as hypotonia, and variable degrees of developmental delay. CC {ECO:0000269|PubMed:25683120, ECO:0000269|PubMed:25864427, CC ECO:0000269|PubMed:31409833, ECO:0000269|PubMed:32698188}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the NALCN family. {ECO:0000305}. CC -!- CAUTION: NALCN was also originally reported to be a voltage- CC independent, cation-nonselective channel which is permeable to sodium, CC potassium and calcium ions (PubMed:17448995). However, NALCN is CC recently reported to be selective only for monovalent cations and to be CC blocked by extracellular divalent cations (PubMed:32494638). Futhemore, CC coexpression of NALCN, UNC79, UNC80, and NALF1 results in voltage- CC dependent NALCN currents (PubMed:32494638, PubMed:31409833). CC {ECO:0000269|PubMed:17448995, ECO:0000269|PubMed:31409833, CC ECO:0000269|PubMed:32494638}. CC -!- SEQUENCE CAUTION: CC Sequence=BAD18738.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY141972; AAN10255.1; -; mRNA. DR EMBL; AL138707; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL354891; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL356778; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471085; EAX09045.1; -; Genomic_DNA. DR EMBL; BC028390; AAH28390.1; -; mRNA. DR EMBL; BC064343; AAH64343.1; -; mRNA. DR EMBL; AE014293; AAN16023.1; -; Genomic_DNA. DR EMBL; AK172752; BAD18738.1; ALT_INIT; mRNA. DR CCDS; CCDS9498.1; -. [Q8IZF0-1] DR RefSeq; NP_443099.1; NM_052867.2. [Q8IZF0-1] DR RefSeq; XP_011519370.1; XM_011521068.2. DR PDB; 6XIW; EM; 2.80 A; A=1-1738. DR PDB; 7CM3; EM; 3.10 A; A=1-1738. DR PDB; 7SX3; EM; 3.10 A; A=1-1738. DR PDB; 7SX4; EM; 3.50 A; A=1-1738. DR PDB; 7WJI; EM; 4.50 A; C=1-1738. DR PDBsum; 6XIW; -. DR PDBsum; 7CM3; -. DR PDBsum; 7SX3; -. DR PDBsum; 7SX4; -. DR PDBsum; 7WJI; -. DR AlphaFoldDB; Q8IZF0; -. DR EMDB; EMD-22203; -. DR EMDB; EMD-30400; -. DR SMR; Q8IZF0; -. DR BioGRID; 129228; 5. DR ComplexPortal; CPX-2341; NALCN channelosome complex. DR IntAct; Q8IZF0; 4. DR MINT; Q8IZF0; -. DR STRING; 9606.ENSP00000251127; -. DR GuidetoPHARMACOLOGY; 750; -. DR TCDB; 1.A.1.11.15; the voltage-gated ion channel (vic) superfamily. DR GlyCosmos; Q8IZF0; 3 sites, No reported glycans. DR GlyGen; Q8IZF0; 4 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q8IZF0; -. DR PhosphoSitePlus; Q8IZF0; -. DR SwissPalm; Q8IZF0; -. DR BioMuta; NALCN; -. DR DMDM; 74750791; -. DR jPOST; Q8IZF0; -. DR MassIVE; Q8IZF0; -. DR PaxDb; 9606-ENSP00000251127; -. DR PeptideAtlas; Q8IZF0; -. DR ProteomicsDB; 71335; -. [Q8IZF0-1] DR Antibodypedia; 25282; 110 antibodies from 15 providers. DR DNASU; 259232; -. DR Ensembl; ENST00000251127.11; ENSP00000251127.6; ENSG00000102452.18. [Q8IZF0-1] DR Ensembl; ENST00000376200.6; ENSP00000365373.5; ENSG00000102452.18. [Q8IZF0-3] DR GeneID; 259232; -. DR KEGG; hsa:259232; -. DR MANE-Select; ENST00000251127.11; ENSP00000251127.6; NM_052867.4; NP_443099.1. DR UCSC; uc001vox.2; human. [Q8IZF0-1] DR AGR; HGNC:19082; -. DR CTD; 259232; -. DR DisGeNET; 259232; -. DR GeneCards; NALCN; -. DR HGNC; HGNC:19082; NALCN. DR HPA; ENSG00000102452; Tissue enhanced (brain). DR MalaCards; NALCN; -. DR MIM; 611549; gene. DR MIM; 615419; phenotype. DR MIM; 616266; phenotype. DR neXtProt; NX_Q8IZF0; -. DR OpenTargets; ENSG00000102452; -. DR Orphanet; 562528; Congenital limbs-face contractures-hypotonia-developmental delay syndrome. DR Orphanet; 1146; Distal arthrogryposis type 1. DR Orphanet; 2053; Freeman-Sheldon syndrome. DR Orphanet; 371364; Hypotonia-speech impairment-severe cognitive delay syndrome. DR Orphanet; 1147; Sheldon-Hall syndrome. DR PharmGKB; PA162396840; -. DR VEuPathDB; HostDB:ENSG00000102452; -. DR eggNOG; KOG2301; Eukaryota. DR GeneTree; ENSGT00940000156023; -. DR HOGENOM; CLU_000984_0_0_1; -. DR InParanoid; Q8IZF0; -. DR OMA; TLFIAWN; -. DR OrthoDB; 1110761at2759; -. DR PhylomeDB; Q8IZF0; -. DR TreeFam; TF312843; -. DR PathwayCommons; Q8IZF0; -. DR Reactome; R-HSA-2672351; Stimuli-sensing channels. DR SignaLink; Q8IZF0; -. DR SIGNOR; Q8IZF0; -. DR BioGRID-ORCS; 259232; 6 hits in 1147 CRISPR screens. DR ChiTaRS; NALCN; human. DR GenomeRNAi; 259232; -. DR Pharos; Q8IZF0; Tchem. DR PRO; PR:Q8IZF0; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; Q8IZF0; Protein. DR Bgee; ENSG00000102452; Expressed in middle temporal gyrus and 143 other cell types or tissues. DR ExpressionAtlas; Q8IZF0; baseline and differential. DR GO; GO:0034702; C:monoatomic ion channel complex; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0022840; F:leak channel activity; ISS:UniProtKB. DR GO; GO:0005261; F:monoatomic cation channel activity; ISS:UniProtKB. DR GO; GO:0005272; F:sodium channel activity; TAS:Reactome. DR GO; GO:0005248; F:voltage-gated sodium channel activity; IDA:UniProtKB. DR GO; GO:0070588; P:calcium ion transmembrane transport; ISS:UniProtKB. DR GO; GO:0034220; P:monoatomic ion transmembrane transport; TAS:Reactome. DR GO; GO:0032224; P:positive regulation of synaptic transmission, cholinergic; IBA:GO_Central. DR GO; GO:0032230; P:positive regulation of synaptic transmission, GABAergic; IBA:GO_Central. DR GO; GO:0071805; P:potassium ion transmembrane transport; ISS:UniProtKB. DR GO; GO:0060075; P:regulation of resting membrane potential; ISS:UniProtKB. DR GO; GO:0035725; P:sodium ion transmembrane transport; ISS:UniProtKB. DR Gene3D; 1.10.287.70; -; 4. DR Gene3D; 1.10.238.10; EF-hand; 1. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 4. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR028823; NALCN. DR InterPro; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR46141:SF1; SODIUM LEAK CHANNEL NALCN; 1. DR PANTHER; PTHR46141; SODIUM LEAK CHANNEL NON-SELECTIVE PROTEIN; 1. DR Pfam; PF00520; Ion_trans; 4. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 4. DR Genevisible; Q8IZF0; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Coiled coil; KW Disease variant; Disulfide bond; Glycoprotein; Ion channel; Ion transport; KW Membrane; Neurodegeneration; Reference proteome; Repeat; Sodium; KW Sodium channel; Sodium transport; Transmembrane; Transmembrane helix; KW Transport; Voltage-gated channel. FT CHAIN 1..1738 FT /note="Sodium leak channel NALCN" FT /id="PRO_0000314010" FT TOPO_DOM 1..36 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 37..57 FT /note="Helical; Name=S1 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 58..65 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 66..90 FT /note="Helical; Name=S2 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 91..106 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 107..129 FT /note="Helical; Name=S3 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 130..137 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 138..158 FT /note="Helical; Voltage-sensor; Name=S4 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 159..173 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 174..199 FT /note="Helical; Name=S5 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 200..269 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT INTRAMEM 270..289 FT /note="Pore-forming" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 290..294 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 295..322 FT /note="Helical; Name=S6 of repeat I" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 323..382 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 383..403 FT /note="Helical; Name=S1 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 404..416 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 417..439 FT /note="Helical; Name=S2 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 440..447 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 448..468 FT /note="Helical; Name=S3 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 469..472 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 473..492 FT /note="Helical; Voltage-sensor; Name=S4 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 493..502 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 503..530 FT /note="Helical; Name=S5 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 531..543 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT INTRAMEM 544..563 FT /note="Pore-forming" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 564..569 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 570..599 FT /note="Helical; Name=S6 of repeat II" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 600..886 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 887..906 FT /note="Helical; Name=S1 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 907..915 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 916..939 FT /note="Helical; Name=S2 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 940..947 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 948..972 FT /note="Helical; Name=S3 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 973..980 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 981..1003 FT /note="Helical; Voltage-sensor; Name=S4 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1004..1015 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1016..1039 FT /note="Helical; Name=S5 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1040..1104 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT INTRAMEM 1105..1124 FT /note="Pore-forming" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1125..1129 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1130..1159 FT /note="Helical; Name=S6 of repeat III" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1160..1210 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1211..1227 FT /note="Helical; Name=S1 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1228..1236 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1237..1260 FT /note="Helical; Name=S2 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1261..1271 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1272..1293 FT /note="Helical; Name=S3 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1294..1296 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1297..1318 FT /note="Helical; Voltage-sensor; Name=S4 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1319..1331 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1332..1357 FT /note="Helical; Name=S5 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1358..1378 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT INTRAMEM 1379..1398 FT /note="Pore-forming" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1399..1420 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TRANSMEM 1421..1447 FT /note="Helical; Name=S6 of repeat IV" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT TOPO_DOM 1448..1738 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0007744|PDB:6XIW" FT REGION 762..785 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1611..1678 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 795..830 FT /evidence="ECO:0000255" FT COMPBIAS 1611..1651 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 210 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:33203861, FT ECO:0007744|PDB:7CM3" FT CARBOHYD 216 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:33203861, FT ECO:0007744|PDB:7CM3" FT CARBOHYD 1064 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0000269|PubMed:33203861, ECO:0007744|PDB:6XIW, FT ECO:0007744|PDB:7CM3" FT DISULFID 207..239 FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0000269|PubMed:33203861, ECO:0007744|PDB:6XIW, FT ECO:0007744|PDB:7CM3" FT DISULFID 229..245 FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0000269|PubMed:33203861, ECO:0007744|PDB:6XIW, FT ECO:0007744|PDB:7CM3" FT DISULFID 1046..1057 FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0000269|PubMed:33203861, ECO:0007744|PDB:6XIW, FT ECO:0007744|PDB:7CM3" FT DISULFID 1405..1417 FT /evidence="ECO:0000269|PubMed:32698188, FT ECO:0000269|PubMed:33203861, ECO:0007744|PDB:6XIW, FT ECO:0007744|PDB:7CM3" FT VAR_SEQ 216..218 FT /note="NVT -> LSL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_030188" FT VAR_SEQ 219..1738 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_030189" FT VAR_SEQ 589..668 FT /note="ILLSLFVAVILDNLELDEDLKKLKQLKQSEANADTKEKLPLRLRIFEKFPNR FT PQMVKISKLPSDFTVPKIRESFMKQFID -> PPSLIRDLCGTQDACPSCLPLQPPNHL FT PGSQTLARLTHQALTTPPGMRSSQLFSKISLLLGICVAWESILGSLSLSHNLQ (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_030190" FT VAR_SEQ 669..1738 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_030191" FT VARIANT 177 FT /note="Q -> P (in CLIFAHDD; dbSNP:rs786203984)" FT /evidence="ECO:0000269|PubMed:25683120" FT /id="VAR_073361" FT VARIANT 312 FT /note="L -> I (in CLIFAHDD; dbSNP:rs878853134)" FT /evidence="ECO:0000269|PubMed:25683120" FT /id="VAR_073362" FT VARIANT 312 FT /note="L -> V (found in patients with neurodevelopmental FT disease and hypotonia; uncertain significance)" FT /evidence="ECO:0000269|PubMed:26763878" FT /id="VAR_076674" FT VARIANT 313 FT /note="V -> G (in CLIFAHDD; dbSNP:rs786203985)" FT /evidence="ECO:0000269|PubMed:25683120" FT /id="VAR_073363" FT VARIANT 317 FT /note="F -> C (found in patients with distal arthrogryposis FT and central hypertonia; uncertain significance; FT dbSNP:rs1594616249)" FT /evidence="ECO:0000269|PubMed:27214504" FT /id="VAR_076675" FT VARIANT 509 FT /note="L -> S (in CLIFAHDD and IHPRF1; nearly eliminates FT wild-type protein expression; dominant-negative mutation; FT decreases membrane expression; induces higher current FT density and slower inactivation; dbSNP:rs786203987)" FT /evidence="ECO:0000269|PubMed:25683120, FT ECO:0000269|PubMed:31409833" FT /id="VAR_073364" FT VARIANT 578 FT /note="Y -> S (in CLIFAHDD and IHPRF1; nearly eliminates FT wild-type protein expression; dominant-negative mutation; FT decreases membrane expressioninduces higher current density FT and slower inactivation; dbSNP:rs786203988)" FT /evidence="ECO:0000269|PubMed:25683120, FT ECO:0000269|PubMed:31409833" FT /id="VAR_073365" FT VARIANT 590 FT /note="L -> F (in CLIFAHDD; dbSNP:rs786203986)" FT /evidence="ECO:0000269|PubMed:25683120, FT ECO:0000269|PubMed:32698188" FT /id="VAR_073366" FT VARIANT 595 FT /note="V -> F (found in patients with distal arthrogryposis FT and central hypertonia; uncertain significance; FT dbSNP:rs1594368753)" FT /evidence="ECO:0000269|PubMed:27214504" FT /id="VAR_076676" FT VARIANT 1020 FT /note="V -> F (found in patients with neurodevelopmental FT disease and hypotonia; uncertain significance)" FT /evidence="ECO:0000269|PubMed:26763878" FT /id="VAR_076677" FT VARIANT 1165 FT /note="T -> P (in CLIFAHDD; dbSNP:rs878853128)" FT /evidence="ECO:0000269|PubMed:25683120" FT /id="VAR_073367" FT VARIANT 1181 FT /note="R -> Q (in CLIFAHDD; uncertain significance; also FT found in patients with neurodevelopmental disease and FT hypotonia; uncertain significance; dbSNP:rs786201003)" FT /evidence="ECO:0000269|PubMed:25864427, FT ECO:0000269|PubMed:26763878, ECO:0000269|PubMed:32698188" FT /id="VAR_076678" FT VARIANT 1287 FT /note="W -> L (in IHPRF1; loss of function; FT dbSNP:rs587777068)" FT /evidence="ECO:0000269|PubMed:24075186, FT ECO:0000269|PubMed:31409833, ECO:0000269|PubMed:32698188" FT /id="VAR_070599" FT VARIANT 1446 FT /note="I -> M (in CLIFAHDD; dbSNP:rs878853127)" FT /evidence="ECO:0000269|PubMed:25683120, FT ECO:0000269|PubMed:32698188" FT /id="VAR_073368" FT MUTAGEN 146 FT /note="R->Q: Affects voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 152 FT /note="R->Q: Affects voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 155 FT /note="R->Q: Affects voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 280 FT /note="E->A: Drastically more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 325 FT /note="F->A: Increases channel activity." FT /evidence="ECO:0000269|PubMed:33203861" FT MUTAGEN 328 FT /note="I->W: Increases channel activity." FT /evidence="ECO:0000269|PubMed:33203861" FT MUTAGEN 332 FT /note="F->A: No effect on the channel activity." FT /evidence="ECO:0000269|PubMed:33203861" FT MUTAGEN 481 FT /note="R->Q: Exhibits altered current kinetics." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 484 FT /note="R->Q: Does not exhibited altered current kinetics." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 487 FT /note="K->Q: Does not exhibited altered current kinetics." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 504 FT /note="K->D,A: Decreases channel activity." FT /evidence="ECO:0000269|PubMed:33203861" FT MUTAGEN 505 FT /note="K->A: Decreases channel activity." FT /evidence="ECO:0000269|PubMed:33203861" FT MUTAGEN 554 FT /note="E->A: Drastically more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 558 FT /note="D->A: Moderately more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 561 FT /note="D->A: No effect on the blockage of NALCN pore by FT Ca(2+)." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 989 FT /note="R->Q: Does not affect the voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 992 FT /note="R->Q: Does not affect the voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 995 FT /note="R->Q: Does not affect the voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 1115 FT /note="K->A: No effect on the blockage of NALCN pore by FT Ca(2+)." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 1119 FT /note="E->A: Moderately more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 1310 FT /note="R->Q: Does not affect the voltage sensitivity." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 1389 FT /note="E->A: Moderately more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT MUTAGEN 1390 FT /note="D->A: Drastically more sensitive to Ca(2+) block." FT /evidence="ECO:0000269|PubMed:32494638" FT TURN 32..34 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 37..55 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 58..63 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 67..90 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 108..129 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 130..133 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 138..143 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 146..149 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 150..153 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 156..158 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 160..162 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 164..199 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 205..211 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 219..221 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 231..236 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 243..247 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 255..258 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 262..265 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 266..277 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 282..292 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 295..308 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 309..311 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 312..333 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 355..357 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 374..376 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 378..381 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 384..402 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 417..446 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 449..464 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 467..471 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 475..480 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 481..488 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 490..499 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 503..528 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 537..539 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 540..552 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 553..555 FT /evidence="ECO:0007829|PDB:7SX4" FT HELIX 556..566 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 569..571 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 572..588 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 590..602 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 606..615 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 630..632 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 633..636 FT /evidence="ECO:0007829|PDB:7SX3" FT STRAND 647..649 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 660..668 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 714..717 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 719..739 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 818..829 FT /evidence="ECO:0007829|PDB:7SX3" FT STRAND 830..834 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 836..838 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 847..855 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 878..882 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 887..903 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 908..910 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 912..914 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 916..940 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 942..945 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 949..952 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 953..971 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 978..980 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 981..988 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 989..994 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 995..999 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1001..1011 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1014..1039 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1040..1042 FT /evidence="ECO:0007829|PDB:7SX3" FT STRAND 1045..1048 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1054..1056 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1059..1065 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1069..1071 FT /evidence="ECO:0007829|PDB:7CM3" FT STRAND 1082..1087 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1101..1112 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1117..1127 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1130..1132 FT /evidence="ECO:0007829|PDB:7SX3" FT HELIX 1133..1143 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1144..1146 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1147..1163 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1166..1168 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1170..1184 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1198..1207 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1210..1223 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1224..1228 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1233..1235 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 1238..1262 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1264..1268 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1272..1291 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1292..1294 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1297..1312 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1313..1316 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1319..1334 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1336..1356 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1367..1370 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1375..1386 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1387..1390 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1391..1397 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1412..1414 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 1420..1436 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1438..1453 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1459..1461 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1464..1477 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1479..1481 FT /evidence="ECO:0007829|PDB:7SX3" FT STRAND 1482..1485 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1489..1496 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1499..1501 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1505..1507 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1509..1521 FT /evidence="ECO:0007829|PDB:6XIW" FT TURN 1522..1524 FT /evidence="ECO:0007829|PDB:6XIW" FT STRAND 1525..1529 FT /evidence="ECO:0007829|PDB:7CM3" FT HELIX 1530..1539 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1544..1547 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1550..1570 FT /evidence="ECO:0007829|PDB:6XIW" FT HELIX 1590..1601 FT /evidence="ECO:0007829|PDB:6XIW" SQ SEQUENCE 1738 AA; 200331 MW; 296BB66C9E443151 CRC64; MLKRKQSSRV EAQPVTDFGP DESLSDNADI LWINKPWVHS LLRICAIISV ISVCMNTPMT FEHYPPLQYV TFTLDTLLMF LYTAEMIAKM HIRGIVKGDS SYVKDRWCVF DGFMVFCLWV SLVLQVFEIA DIVDQMSPWG MLRIPRPLIM IRAFRIYFRF ELPRTRITNI LKRSGEQIWS VSIFLLFFLL LYGILGVQMF GTFTYHCVVN DTKPGNVTWN SLAIPDTHCS PELEEGYQCP PGFKCMDLED LGLSRQELGY SGFNEIGTSI FTVYEAASQE GWVFLMYRAI DSFPRWRSYF YFITLIFFLA WLVKNVFIAV IIETFAEIRV QFQQMWGSRS STTSTATTQM FHEDAAGGWQ LVAVDVNKPQ GRAPACLQKM MRSSVFHMFI LSMVTVDVIV AASNYYKGEN FRRQYDEFYL AEVAFTVLFD LEALLKIWCL GFTGYISSSL HKFELLLVIG TTLHVYPDLY HSQFTYFQVL RVVRLIKISP ALEDFVYKIF GPGKKLGSLV VFTASLLIVM SAISLQMFCF VEELDRFTTF PRAFMSMFQI LTQEGWVDVM DQTLNAVGHM WAPVVAIYFI LYHLFATLIL LSLFVAVILD NLELDEDLKK LKQLKQSEAN ADTKEKLPLR LRIFEKFPNR PQMVKISKLP SDFTVPKIRE SFMKQFIDRQ QQDTCCLLRS LPTTSSSSCD HSKRSAIEDN KYIDQKLRKS VFSIRARNLL EKETAVTKIL RACTRQRMLS GSFEGQPAKE RSILSVQHHI RQERRSLRHG SNSQRISRGK SLETLTQDHS NTVRYRNAQR EDSEIKMIQE KKEQAEMKRK VQEEELRENH PYFDKPLFIV GREHRFRNFC RVVVRARFNA SKTDPVTGAV KNTKYHQLYD LLGLVTYLDW VMIIVTICSC ISMMFESPFR RVMHAPTLQI AEYVFVIFMS IELNLKIMAD GLFFTPTAVI RDFGGVMDIF IYLVSLIFLC WMPQNVPAES GAQLLMVLRC LRPLRIFKLV PQMRKVVREL FSGFKEIFLV SILLLTLMLV FASFGVQLFA GKLAKCNDPN IIRREDCNGI FRINVSVSKN LNLKLRPGEK KPGFWVPRVW ANPRNFNFDN VGNAMLALFE VLSLKGWVEV RDVIIHRVGP IHGIYIHVFV FLGCMIGLTL FVGVVIANFN ENKGTALLTV DQRRWEDLKS RLKIAQPLHL PPRPDNDGFR AKMYDITQHP FFKRTIALLV LAQSVLLSVK WDVEDPVTVP LATMSVVFTF IFVLEVTMKI IAMSPAGFWQ SRRNRYDLLV TSLGVVWVVL HFALLNAYTY MMGACVIVFR FFSICGKHVT LKMLLLTVVV SMYKSFFIIV GMFLLLLCYA FAGVVLFGTV KYGENINRHA NFSSAGKAIT VLFRIVTGED WNKIMHDCMV QPPFCTPDEF TYWATDCGNY AGALMYFCSF YVIIAYIMLN LLVAIIVENF SLFYSTEEDQ LLSYNDLRHF QIIWNMVDDK REGVIPTFRV KFLLRLLRGR LEVDLDKDKL LFKHMCYEME RLHNGGDVTF HDVLSMLSYR SVDIRKSLQL EELLAREQLE YTIEEEVAKQ TIRMWLKKCL KRIRAKQQQS CSIIHSLRES QQQELSRFLN PPSIETTQPS EDTNANSQDN SMQPETSSQQ QLLSPTLSDR GGSRQDAADA GKPQRKFGQW RLPSAPKPIS HSVSSVNLRF GGRTTMKSVV CKMNPMTDAA SCGSEVKKWW TRQLTVESDE SGDDLLDI //