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Regulatory pathways and chemicals affecting NALCN function

Apologies in advance to reviewers, I took notes on a number of articles and have been drafting from my notes, but I need to go back and sort out where I sourced all the info.

Small Edits to Make

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Add third row to "Classification" Something to the tune of the following:
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Leak Sodium Channels NALCN Constantly open with variable permittivity
"Role in action potential" is kinda poorly worded (fix it myself?) at least add something along the lines of:
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Leak channels additionally contribute to the action potential by controlling the resting potential of a neuron, effectively regulating the excitability of a neuron.[1]

"Pharmacological modulation" will need specifics for NALCN (or include it later in it's own section?) in addition, expand the "blockers" section to be more than a reference to the other article:
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Blockers[edit]

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Main article: Sodium channel blocker

Activators[edit]

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See also: Sodium channel opener

The following naturally produced substances persistently activate (open) sodium channels:

The following increase the activity of the sodium leak channel through activation of GPCRs

Sodium leak channel (NALCN)

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Sodium leak channels do not show any voltage or ligand gating. Instead, they are always open or "leaking" a small background current to regulate the resting membrane potential of a neuron.[1] In most animals, a single gene encodes the NALCN (sodium leak channel, nonselective) protein.[6]

Structural and functional differences

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Despite following the same basic structure as other sodium channels, NALCN is not sensitive to voltage changes. The voltage-sensitive S4 transmembrane domain of NALCN has fewer positively charged amino acids (13 instead of a voltage gated channel's 21) possibly explaining it's voltage insensitivity.[1] NALCN is also far less selective for Na+ ions and is permeable to Ca2+ and K+ ions. The EEKE amino acid motif in the pore filter domain of NALCN is similar to both the EEEE motif of voltage-gated calcium channel and the DEKA motif of the voltage-gated sodium channel, possibly explaining its lack of selectivity.[6]

NALCN is not blocked by many common sodium channel blockers, including tetrodotoxin.[3] NALCN is blocked nonspecifically by both Gd3+ and verapamil.[3] Substance P and Neurotensin both activate Src family kinases through their respective GPCRs (independent of the coupled G-proteins) which in turn increase the permeability of NALCN through UNC80 activation.[5] Acetylcholine can also increase NALCN activity through M3 muscarinic acetylcholine receptors. Higher levels of extracellular Ca2+ decrease the permeability of NALCN by activating CaSR which inhibits UNC80.[2]

Protein Complex

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NALCN complexes with the proteins UNC79, UNC80, and FAM155A.[7][8][9] UNC79 appears to be linked to membrane stability of NALCN and linkage with UNC 80.[8] UNC80 mediates chemical modulation of NALCN through multiple pathways.[1][2][4][5] FAM155A helps protein folding in the endoplasmic reticulum, chaperones transport to the axon, and contributes to membrane stability.[9]

Biological function

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The resting membrane potential of a neuron is usually -60mV to -80mV, driven primarily by the K+ potential at -90mV. The depolarization from the K+ potential is due primarily to a small Na+ leak current. About 70% of this current is through NALCN.[3] Increasing NALCN permeability lowers the resting membrane potential, bringing it closer to the trigger of an action potential (-55mV), thus increasing the excitability of a neuron.

Role in pathology

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Mutations to NALCN lead to severe disruptions to respiratory rhythm in mice[3] and altered circadian locomotion in flies.[10] Mutations to NALCN have also been linked to multiple severe developmental disorders[11] and cervical dystonia.[12] Schizophrenia and bipolar disorder are also linked to mutations to NALCN.[13]

References

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  1. ^ a b c d Ren, Dejian (2011-12-22). "Sodium Leak Channels in Neuronal Excitability and Rhythmic Behaviors". Neuron. 72 (6): 899–911. doi:10.1016/j.neuron.2011.12.007. ISSN 0896-6273. PMC 3247702. PMID 22196327.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c Lu, Boxun; Zhang, Qi; Wang, Haikun; Wang, Yan; Nakayama, Manabu; Ren, Dejian (2010-11-04). "Extracellular Calcium Controls Background Current and Neuronal Excitability via an UNC79-UNC80-NALCN Cation Channel Complex". Neuron. 68 (3): 488–499. doi:10.1016/j.neuron.2010.09.014. ISSN 0896-6273. PMC 2987630. PMID 21040849.{{cite journal}}: CS1 maint: PMC format (link)
  3. ^ a b c d e f Lu, Boxun; Su, Yanhua; Das, Sudipto; Liu, Jin; Xia, Jingsheng; Ren, Dejian (2007-04-20). "The Neuronal Channel NALCN Contributes Resting Sodium Permeability and Is Required for Normal Respiratory Rhythm". Cell. 129 (2): 371–383. doi:10.1016/j.cell.2007.02.041. ISSN 0092-8674.
  4. ^ a b Swayne, Leigh Anne; Mezghrani, Alexandre; Varrault, Annie; Chemin, Jean; Bertrand, Gyslaine; Dalle, Stephane; Bourinet, Emmanuel; Lory, Philippe; Miller, Richard J; Nargeot, Joel; Monteil, Arnaud (2009-07-03). "The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic β‐cell line". EMBO reports. 10 (8): 873–880. doi:10.1038/embor.2009.125. ISSN 1469-221X. PMC 2710536. PMID 19575010.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ a b c d Lu, Boxun; Su, Yanhua; Das, Sudipto; Wang, Haikun; Wang, Yan; Liu, Jin; Ren, Dejian (2009-02-05). "Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80". Nature. 457 (7230): 741–744. doi:10.1038/nature07579. ISSN 1476-4687. PMC 2810458. PMID 19092807.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ a b Lee, Jung-Ha; Cribbs, Leanne L.; Perez-Reyes, Edward (1999-02-26). "Cloning of a novel four repeat protein related to voltage‐gated sodium and calcium channels". FEBS Letters. 445 (2–3): 231–236. doi:10.1016/S0014-5793(99)00082-4. ISSN 0014-5793.
  7. ^ Yeh, Edward; Ng, Sharon; Zhang, Mi; Bouhours, Magali; Wang, Ying; Wang, Min; Hung, Wesley; Aoyagi, Kyota; Melnik-Martinez, Katya; Li, Michelle; Liu, Fang; Schafer, William R.; Zhen, Mei (2008-03-11). "A Putative Cation Channel, NCA-1, and a Novel Protein, UNC-80, Transmit Neuronal Activity in C. elegans". PLOS Biology. 6 (3): e55. doi:10.1371/journal.pbio.0060055. ISSN 1545-7885. PMC 2265767. PMID 18336069.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  8. ^ a b Humphrey, John A.; Hamming, Kevin S.; Thacker, Colin M.; Scott, Robert L.; Sedensky, Margaret M.; Snutch, Terrance P.; Morgan, Phil G.; Nash, Howard A. (2007-04-03). "A Putative Cation Channel and Its Novel Regulator: Cross-Species Conservation of Effects on General Anesthesia". Current Biology. 17 (7): 624–629. doi:10.1016/j.cub.2007.02.037. ISSN 0960-9822.
  9. ^ a b Xie, Jiongfang; Ke, Meng; Xu, Lizhen; Lin, Shiyi; Huang, Jin; Zhang, Jiabei; Yang, Fan; Wu, Jianping; Yan, Zhen (2020-11-17). "Structure of the human sodium leak channel NALCN in complex with FAM155A". Nature Communications. 11 (1): 5831. doi:10.1038/s41467-020-19667-z. ISSN 2041-1723. PMC 7672056. PMID 33203861.{{cite journal}}: CS1 maint: PMC format (link)
  10. ^ Lear, Bridget C.; Lin, Jui-Ming; Keath, J. Russel; McGill, Jermaine J.; Raman, Indira M.; Allada, Ravi (2005-12-22). "The Ion Channel Narrow Abdomen Is Critical for Neural Output of the Drosophila Circadian Pacemaker". Neuron. 48 (6): 965–976. doi:10.1016/j.neuron.2005.10.030. ISSN 0896-6273.
  11. ^ Al-Sayed, Moeenaldeen D.; Al-Zaidan, Hamad; Albakheet, AlBandary; Hakami, Hana; Kenana, Rosan; Al-Yafee, Yusra; Al-Dosary, Mazhor; Qari, Alya; Al-Sheddi, Tarfa; Al-Muheiza, Muhammed; Al-Qubbaj, Wafa; Lakmache, Yamina; Al-Hindi, Hindi; Ghaziuddin, Muhammad; Colak, Dilek (2013-10-03). "Mutations in NALCN Cause an Autosomal-Recessive Syndrome with Severe Hypotonia, Speech Impairment, and Cognitive Delay". The American Journal of Human Genetics. 93 (4): 721–726. doi:10.1016/j.ajhg.2013.08.001. ISSN 0002-9297. PMC 3791267. PMID 24075186.{{cite journal}}: CS1 maint: PMC format (link)
  12. ^ Mok, Kin Y.; Schneider, Susanne A.; Trabzuni, Daniah; Stamelou, Maria; Edwards, Mark; Kasperaviciute, Dalia; Pickering‐Brown, Stuart; Silverdale, Monty; Hardy, John; Bhatia, Kailash P. (2014-02-01). "Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel". Movement Disorders. 29 (2): 245–251. doi:10.1002/mds.25732. ISSN 0885-3185. PMC 4208301. PMID 24227479.{{cite journal}}: CS1 maint: PMC format (link)
  13. ^ Wang, Ke-Sheng; Liu, Xue-Feng; Aragam, Nagesh (2010-12-01). "A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder". Schizophrenia Research. 124 (1): 192–199. doi:10.1016/j.schres.2010.09.002. ISSN 0920-9964.
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