Dataset Information

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

ABSTRACT: Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.

SUBMITTER: Musial TF

PROVIDER: S-EPMC6434702 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Musial Timothy F TF Molina-Campos Elizabeth E Bean Linda A LA Ybarra Natividad N Borenstein Ronen R Russo Matthew L ML Buss Eric W EW Justus Daniel D Neuman Krystina M KM Ayala Gelique D GD Mullen Sheila A SA Voskobiynyk Yuliya Y Tulisiak Christopher T CT Fels Jasmine A JA Corbett Nicola J NJ Carballo Gabriel G Kennedy Colette D CD Popovic Jelena J Ramos-Franco Josefina J Fill Michael M Pergande Melissa R MR Borgia Jeffrey A JA Corbett Grant T GT Pahan Kalipada K Han Ye Y Chetkovich Dane M DM Vassar Robert J RJ Byrne Richard W RW Matthew Oh M M Stoub Travis R TR Remy Stefan S Disterhoft John F JF Nicholson Daniel A DA

Neurobiology of learning and memory 20180612

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal ...[more]

PMID: 29906573

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Project description:KCNMA1 encodes the pore-forming α subunit of the "Big K+" (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1-/- ) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "KCNMA1-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

Dataset Information

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Publications

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

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