Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain

Abstract

The α7 nicotinic acetylcholine receptor (α7 nAChR) is highly expressed in the brain, where it maintains various neuronal functions including (but not limited to) learning and memory. In addition, the protein expression levels of α7 nAChRs are altered in various brain disorders. The classic rule governing α7 nAChR assembly in the mammalian brain was that it was assembled from five α7 subunits to form a homomeric receptor pentamer. However, emerging evidence demonstrates the presence of heteromeric α7 nAChRs in heterologously expressed systems and naturally in brain neurons, where α7 subunits are co-assembled with β2 subunits to form a novel type of α7β2 nAChR. Interestingly, the α7β2 nAChR exhibits distinctive function and pharmacology from traditional homomeric α7 nAChRs. We review recent advances in probing the distribution, function, pharmacology, pathophysiology, and stoichiometry of the heteromeric α7β2 nAChR, which have provided new insights into the understanding of a novel target of cholinergic signaling.

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…It should also be noted that until recently, Abeta was thought to only interact with α7 homo-pentameric nAChRs. After more than 20 years of speculation that endogenous α7* receptors may be heteromeric, α7β2* receptors have now been established as a potentially significant component of the brain nAChRs (Wu et al, 2016). Of particular interest is the presence of α7β2* in BFCNs and the fact that α7β2* receptors have up to 100-fold greater sensitivity to pathological Abeta peptides than do homomeric α7 nAChRs.…”

“…Cellular mechanisms of cholinergic neuronal loss and subsequent disruption of target hippocampal & cortical domains. Possible mechanisms thought to underlie early loss of cholinergic projections in an animal model of AD-like dementia: Aβ induced excitotoxicity mediated by interaction with α7* nAChRs (Hascup & Hascup, 2016; Liu et al, 2016; Wu et al, 2016), and impaired neurotrophin–induced retrograde transport via Rab5 endosome enlargement (Xu et al, 2015). Images for A adapted from human brain atlas (Hawrylycz et al, 2012)…”

Astroglial calcium signalling in Alzheimer's disease

“…Exposure to β-amyloid affects several types of Ca 2+ permeable membrane channels. In particular β-amyloid binds to and modulates Ca 2+ -permeable neuronal acetylcholine receptors in α7 (homomeric), α7β2 and α4β2 compositions; β-amyloid activates α7 receptors in picomolar concentrations, while inhibits the both of above heteromeric receptors in nanomolar concentrations [14,15]. There are certain arguments that β-amyloid excitotoxicity is mediated by extra-synaptic NMDA receptors [16], although this might be an indirect effect (for example, through an inhibition of astroglial glutamate clearance systems [17]).…”

Shared and unique aspects of ligand‐ and voltage‐gated ion‐channel gating

“…Although nAChRs are expressed throughout the body, α7 receptors are especially concentrated in the mammalian brain where they exhibit both ionotropic and metabotropic functions (Wu et al . ; Kabbani & Nichols, ). They are also implicated in several CNS disorders (Dineley et al .…”