A Novel Nicotinic Acetylcholine Receptor Subtype in Basal Forebrain Cholinergic Neurons with High Sensitivity to Amyloid Peptides

Abstract

Nicotinic acetylcholine receptors (nAChRs) containing ␣7 subunits are thought to assemble as homomers. ␣7-nAChR function has been implicated in learning and memory, and alterations of ␣7-nAChR have been found in patients with Alzheimer's disease (AD). Here we report findings consistent with a novel, naturally occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, ␣7 subunits are coexpressed, colocalize, and coassemble with ␤2 subunit(s). Compared with homomeric ␣7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric ␣7␤2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the ␤2 subunit-containing nAChR-selective antagonist, dihydro-␤-erythroidine (DH␤E). Interestingly, presumed, heteromeric ␣7␤2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid ␤ 1-42 (A␤ 1-42 ). Slow whole-cell current kinetics, sensitivity to DH␤E, and specific antagonism by oligomeric A␤ 1-42 also are characteristics of heteromeric ␣7␤2-nAChRs, but not of homomeric ␣7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to A␤ when elicited from MS/DB neurons derived from nAChR ␤2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric ␣7␤2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric A␤ 1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.

α-Conotoxins Identify theα3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells

“…If b2 subunits are present in human adrenal chromaffin cell a3b4* nAChRs, they are likely to be restricted to the fifth or auxiliary position because no pharmacological evidence for an a3-b2 ligandbinding site was found. Additionally, b2 subunits may assemble with a7 subunits to form a7b2 nAChRs, which have recently been identified in rodent and human basal forebrain as well as mouse hippocampal interneurons (Liu et al, 2009b(Liu et al, , 2012Moretti et al, 2014).…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…These receptors may have a presynaptic localisation where they are involved in the direct release of glutamate in the hippocampus and VTA, and of excitatory amino acid in the prefrontal cortex [92], or the indirect release of DA from striatum and prefrontal cortex, and noradrenaline from the hippocampus [93][94][95]) or a subtype has different biophysical and pharmacological properties from those of wild-type basal forebrain neurons, thus indicating that the subunits probably assemble to form a new subtype in the former [96].…”

Rat neuronal nicotinic acetylcholine receptors containing α7 subunit: pharmacological properties of ligand binding and function

“…A careful examination of subunit compositions of α7 receptors in bovine adrenal chromaffin cells supported the possibility of a small population of heteromeric α7 receptors expressed in chromaffin cells [48] . More recently, Liu et al reported the presence of heteromeric α7β2 receptors in rodent basal forebrain cholinergic neurons [23] ; moreover, these receptor are more sensitive than are homomeric receptors to functional blockade by oligomeric Aβ , which would implicate them in Alzheimer's disease. It will be important to determine if there are heteromeric α7* receptors in rat hippocampus and cerebral cortex; and if so, how these heteromeric α7 receptors contribute to the differences in binding profiles between homomeric α7 nAChRs in KXα7R1 cells and native α7* nAChRs.…”

“…The α7 nAChRs have been implicated in a wide range of physiological functions, including neurotransmitter release [15,16] , activation of second messengers, apoptosis and neuroprotection [17,18] . More recent evidence indicates that α7 nAChRs may be directly involved in learning and memory [19,20] , pathology of Alzheimer's disease [21][22][23] , and inflammation [24] . The advance in our understanding of the biological properties and roles of α7* nAChRs has suggested new therapeutic strategies and drug candidates targeting α7 nAChRs for treatment of CNS disorders, including Alzheimer's disease [25,26] .…”