1.A.9.1.6 The α4β2 nicotinic acetylcholine receptor. The NMR structure of the transmembrane domain and the multiple anaesthetic binding sites are known (Bondarenko et al., 2012). Mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; Díaz-Otero et al. 2000).
Nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction,
epilepsy and for neuromuscular blocking agents used during surgery. This system contributes to cognitive functioning through interactions with multiple
neurotransmitter systems and is implicated in various CNS disorders, i.e., schizophrenia and Alzheimer's disease. It provides an extra layer of molecular complexity by existing in two
different stoichiometries determined by the subunit composition. By potentiating the action of an
agonist through binding to an allosteric site, positive allosteric modulators can enhance
cholinergic neurotransmission (Grupe et al. 2015). Most pentameric receptors are heteromeric. Morales-Perez et al. 2016 presented the X-ray crystallographic structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. The side chains of alpha4 L257 (9') and alpha4L264 (16') may beresponsible for the main constrictions in the transmembrane pore (Yu et al. 2019). Mechanistic steps for communication proceed (1) through a signal generated via loop C in the principal subunit, (2) transmitted gradually and cumulatively to loop F of the complementary subunit, and (3) to the TMSs through the M2-M3 linker (Oliveira et al. 2019). A genetic variant of the nicotinic receptor α4-subunit causes sleep-related hyperkinetic epilepsy via increased channel opening (Mazzaferro et al. 2022).
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Accession Number: | P17787 |
Protein Name: | Neuronal acetylcholine receptor subunit beta-2 |
Length: | 502 |
Molecular Weight: | 57019.00 |
Species: | Homo sapiens (Human) [9606] |
Number of TMSs: | 6 |
Location1 / Topology2 / Orientation3: |
Cell junction1 / Multi-pass membrane protein2 |
Substrate |
ion |
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1: MARRCGPVAL LLGFGLLRLC SGVWGTDTEE RLVEHLLDPS RYNKLIRPAT NGSELVTVQL
61: MVSLAQLISV HEREQIMTTN VWLTQEWEDY RLTWKPEEFD NMKKVRLPSK HIWLPDVVLY
121: NNADGMYEVS FYSNAVVSYD GSIFWLPPAI YKSACKIEVK HFPFDQQNCT MKFRSWTYDR
181: TEIDLVLKSE VASLDDFTPS GEWDIVALPG RRNENPDDST YVDITYDFII RRKPLFYTIN
241: LIIPCVLITS LAILVFYLPS DCGEKMTLCI SVLLALTVFL LLISKIVPPT SLDVPLVGKY
301: LMFTMVLVTF SIVTSVCVLN VHHRSPTTHT MAPWVKVVFL EKLPALLFMQ QPRHHCARQR
361: LRLRRRQRER EGAGALFFRE APGADSCTCF VNRASVQGLA GAFGAEPAPV AGPGRSGEPC
421: GCGLREAVDG VRFIADHMRS EDDDQSVSED WKYVAMVIDR LFLWIFVFVC VFGTIGMFLQ
481: PLFQNYTTTT FLHSDHSAPS SK