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Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca²⁺ hyperexcitation.

ABSTRACT: Beta-amyloid (A?) peptide accumulation has long been implicated in the pathogenesis of Alzheimer's disease (AD). Hippocampal network hyperexcitability in the early stages of the disease leads to increased epileptiform activity and eventually cognitive decline. We found that acute application of 250 nM soluble A?42 oligomers increased Ca²⁺ activity in hippocampal neurons in parallel with a significant decrease in activity in A?42-treated interneurons. A potential target of A?42 is the nicotinic acetylcholine receptor (nAChR). Three major subtypes of nAChRs (?7, ?4?2, and ?3?4) have been reported in the human hippocampus. Simultaneous inhibition of both ?7 and ?4?2 nAChRs mimicked the A?42 effects on both excitatory and inhibitory neurons. However, inhibition of all 3 subtypes showed the opposite effect. Importantly, simultaneous activation of ?7 and ?4?2 nAChRs was required to reverse A?42-induced neuronal hyperexcitation. We suggest co-activation of ?7 and ?4?2 nAChRs is required to reverse A?42-induced Ca²⁺ hyperexcitation.

SUBMITTER: Sun JL

PROVIDER: S-EPMC6960326 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca<sup>2+</sup> hyperexcitation.

Sun Julianna L JL Stokoe Sarah A SA Roberts Jessica P JP Sathler Matheus F MF Nip Kaila A KA Shou Jiayi J Ko Kaitlyn K Tsunoda Susan S Kim Seonil S

Neurobiology of aging 20190919

Beta-amyloid (Aβ) peptide accumulation has long been implicated in the pathogenesis of Alzheimer's disease (AD). Hippocampal network hyperexcitability in the early stages of the disease leads to increased epileptiform activity and eventually cognitive decline. We found that acute application of 250 nM soluble Aβ42 oligomers increased Ca<sup>2+</sup> activity in hippocampal neurons in parallel with a significant decrease in activity in Aβ42-treated interneurons. A potential target of Aβ42 is the ...[more]

PMID: 31629115

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Project description:Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the CHRNA5 gene, differentially modulates α4β2* and α3β4* receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human CHRNA5 gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit-and the role of the D398 and N398 variants-plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in Xenopus oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and-more recently-rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2* and α3β4* receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca2+ signaling between α4β2* and α3β4* receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.

Dataset Information

Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca²⁺ hyperexcitation.

Publications

Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca<sup>2+</sup> hyperexcitation.

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Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca2+ hyperexcitation.

Publications

Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca<sup>2+</sup> hyperexcitation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca²⁺ hyperexcitation.