The alpha7 (α-7) nicotinic acetylcholine receptor (alpha-7 nAcChR) of 502 aas is encoded by the CHRNA7 gene. Acetylcholine binding induces conformational changes that result in open channel formation; opening is blocked by α-bungarotoxin. The protein is a homopentamer. It interacts with RIC3 for proper folding and assembly. The nAChR, but not the glycine receptor, GlyR, exhibits hydrophobic gating (Ivanov et al. 2007). Low resolution NMR structures with associated anesthetics have been reported (Bondarenko et al. 2013). Allosteric modulators exhibit up to 5 distinct pharmacological effects (Gill-Thind et al. 2015). Based on pore hydration and size, a high resolution structure for the channel in
the open conformation has been proposed (Chiodo et al. 2015). Agonists reduce dyskinesias in both early- and later-stage Parkinson's disease (Zhang et al. 2015). Monoterpenes inhibit the alpha7 receptor in the order: carveol > thymoquinone > carvacrol > menthone > thymol > limonene > eugenole > pulegone = carvone = vanilin.
Among the monoterpenes, carveol showed the highest potency (Lozon et al. 2016). A revised structural model has been proposed (Newcombe et al. 2017). In humans, exons 5-10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dupalpha7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation (Lasala et al. 2018). alpha7 and dupalpha7 subunits co-assemble into functional heteromeric receptors, in which at least two alpha7 subunits are required for channel opening. Dupalpha7's presence in the pentameric arrangement does not affect the duration of the potentiated events. Using an alpha7 subunit mutant, activation of (alpha7)2(dupalpha7)3 receptors occurs through ACh binding at the alpha7/alpha7 interfacial binding site (Lasala et al. 2018). B-973 is an efficacious type II positive allosteric modulator (PAM) of alpha7 nicotinic acetylcholine receptors that, like 4BP-TQS and its active isomer GAT107, is able to produce direct allosteric activation in addition to potentiation of orthosteric agonist activity, which identifies it as an ago-PAM (Quadri et al. 2018). DB04763, DB08122 and pefloxacin are antagonists (they are NAMs) while furosemide potentiated ACh responses (it is a Pam) (Smelt et al. 2018). At nM concentration, APPsα (amyloid precursor protein) is an allosteric activator of α7-nAChR,
mediated by the C-terminal 16 amino acids (CTα16) (Korte 2019). At µM concentrations, Rice et al. 2019 identified the GABABR1a as a target of
APPsα, binding the sushi 1 domain via a 17–amino acid sequence (17-mer).
These receptors activate opposing downstream cascades. The intrasubunit cavity of the α7 AcChR is important for the activity of type II positive allosteric modulators while the ECD-TMD junction and intersubunit sites are probably important for the activity of type I positive allosteric modulators (Targowska-Duda et al. 2019). Flavonoids are positive allosteric modulators of alpha7 nicotinic receptors (Nielsen et al. 2019). Active and desensitized state conformations have been examined (Chiodo et al. 2018). Modulators are able to activate or deactivate a7 receptors via allosteric binding; they are called positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs) (Al Rawashdah et al. 2019). Functional divergence related sites cluster in the ligand binding domain, the beta2-beta3 linker close to the N-terminal alpha-helix, the intracellular linkers between transmembrane domains, and the "transition zone" (Pan et al. 2019). A series of phosphonate-functionalized 1,2,3-triazoles are positive allosteric modulators of alpha7 nicotinic acetylcholine receptors (Nielsen et al. 2020). The E-1' --> A-1' substitution at the cytoplasmatic selectivity filter strongly affects sodium and chloride permeation in opposite directions, leading to a complete inversion of selectivity. Thus, structural determinants for the observed cationic-to-anionic inversion reveal a key role of the protonation state of residue rings far from the mutation, in the proximity of the hydrophobic channel gate (Cottone et al. 2020).
|Protein Name:||Neuronal acetylcholine receptor subunit alpha-7|
|Species:||Homo sapiens (Human)  |
|Number of TMSs:||4|
|Location1 / Topology2 / Orientation3:
Cell junction1 / Multi-pass membrane protein2
1: MRCSPGGVWL ALAASLLHVS LQGEFQRKLY KELVKNYNPL ERPVANDSQP LTVYFSLSLL
61: QIMDVDEKNQ VLTTNIWLQM SWTDHYLQWN VSEYPGVKTV RFPDGQIWKP DILLYNSADE
121: RFDATFHTNV LVNSSGHCQY LPPGIFKSSC YIDVRWFPFD VQHCKLKFGS WSYGGWSLDL
181: QMQEADISGY IPNGEWDLVG IPGKRSERFY ECCKEPYPDV TFTVTMRRRT LYYGLNLLIP
241: CVLISALALL VFLLPADSGE KISLGITVLL SLTVFMLLVA EIMPATSDSV PLIAQYFAST
301: MIIVGLSVVV TVIVLQYHHH DPDGGKMPKW TRVILLNWCA WFLRMKRPGE DKVRPACQHK
361: QRRCSLASVE MSAVAPPPAS NGNLLYIGFR GLDGVHCVPT PDSGVVCGRM ACSPTHDEHL
421: LHGGQPPEGD PDLAKILEEV RYIANRFRCQ DESEAVCSEW KFAACVVDRL CLMAFSVFTI
481: ICTIGILMSA PNFVEAVSKD FA