User:OtherwiseDrummer/Sodium channel

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.

"Role in action potential" is kinda poorly worded (fix it myself?) at least add something along the lines of:
Leak channels additionally contribute to the action potential by controlling the resting potential of a neuron, effectively regulating the excitability of a neuron.

Blockers[edit]
Main article: Sodium channel blocker


 * TTX
 * Extracellular Ca2+ (NALCN)
 * Gd3+(NALCN)
 * Verapamil (NALCN)

Activators[edit]
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
 * Alkaloid-based toxins
 * aconitine
 * batrachotoxin
 * brevetoxin
 * ciguatoxin
 * delphinine
 * some grayanotoxins, e.g., grayanotoxin I (other granotoxins inactivate or close sodium channels)
 * veratridine


 * Acetylcholine
 * Substance P
 * Neurotensin

Sodium leak channel (NALCN)
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. In most animals, a single gene encodes the NALCN (sodium leak channel, nonselective) protein.

Structural and functional differences
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. 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.

NALCN is not blocked by many common sodium channel blockers, including tetrodotoxin. NALCN is blocked nonspecifically by both Gd3+ and verapamil. 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. 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.

Protein Complex
NALCN complexes with the proteins UNC79, UNC80, and FAM155A. UNC79 appears to be linked to membrane stability of NALCN and linkage with UNC 80. UNC80 mediates chemical modulation of NALCN through multiple pathways. FAM155A helps protein folding in the endoplasmic reticulum, chaperones transport to the axon, and contributes to membrane stability.

Biological function
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. 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
Mutations to NALCN lead to severe disruptions to respiratory rhythm in mice and altered circadian locomotion in flies. Mutations to NALCN have also been linked to multiple severe developmental disorders and cervical dystonia. Schizophrenia and bipolar disorder are also linked to mutations to NALCN.