Inactivity-induced increase in nAChRs upregulates Shal K+ channels to stabilize synaptic potentials

Ping, Yong; Tsunoda, Susan

doi:10.1038/nn.2969

Cited by 31 publications

(47 citation statements)

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“…Loss of specific ion channels in Drosophila has been shown to activate homeostatic transcriptional networks that act to balance excitability (Parrish et al, 2014;Ping and Tsunoda, 2012). In addition, the AZ T-bar itself has been theorized to function as a 'plasticity module' that can undergo structural adjustments in response to changes in synaptic input that, in turn, modify the probability of vesicle release (Wichmann and Sigrist, 2010).…”

Section: Discussionmentioning

confidence: 99%

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic

et al. 2014

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Synaptic scaffold proteins control the localization of ion channels and receptors, and facilitate molecular associations between signaling components that modulate synaptic transmission and plasticity. Here, we define novel roles for a recently described scaffold protein, Dsychronic (DYSC), at the Drosophila larval neuromuscular junction. DYSC is the Drosophila homolog of whirlin/DFNB31, a PDZ domain protein linked to Usher syndrome, the most common form of human deaf-blindness. We show that DYSC is expressed presynaptically and is often localized adjacent to the active zone, the site of neurotransmitter release. Loss of DYSC results in marked alterations in synaptic morphology and cytoskeletal organization. Moreover, active zones are frequently enlarged and misshapen in dysc mutants. Electrophysiological analyses further demonstrate that dysc mutants exhibit substantial increases in both evoked and spontaneous synaptic transmission. We have previously shown that DYSC binds to and regulates the expression of the Slowpoke (SLO) BK potassium channel. Consistent with this, slo mutant larvae exhibit similar alterations in synapse morphology, active zone size and neurotransmission, and simultaneous loss of dysc and slo does not enhance these phenotypes, suggesting that dysc and slo act in a common genetic pathway to modulate synaptic development and output. Our data expand our understanding of the neuronal functions of DYSC and uncover non-canonical roles for the SLO potassium channel at Drosophila synapses.

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Section: Discussionmentioning

confidence: 99%

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic

et al. 2014

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“…We suggest that upregulation of highly calcium-permeable ␣7-nAChR expression and function on glutamatergic presynaptic terminals could lead to increased glutamatergic release responsible for the increased glutamate mEPSC frequency seen in A␤-treated cultures. Other possible mechanisms cannot be ruled out (Ping and Tsunoda, 2012) and warrant further investigation, but we propose a new hypothesis that, in AD brain, aberrantly high deposition of A␤ upregulates ␣7-nAChR expression and function, in turn inducing neural hyperexcitation, perhaps epileptic seizures, and consequent neurotoxicity. If this hypothesis is true, then ␣7-nAChR antagonists should be considered as a potential therapeutic strategy for AD therapy.…”

Section: Specificity Of Effects Of A␤ Exposure On ␣7-nachr Expressionmentioning

confidence: 91%

A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation

et al. 2013

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There is a significantly elevated incidence of epilepsy in Alzheimer's disease (AD). Moreover, there is neural hyperexcitation/synchronization in transgenic mice expressing abnormal levels or forms of amyloid precursor protein and its presumed, etiopathogenic product, amyloid-␤ 1-42 (A␤). However, the underlying mechanisms of how A␤ causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of A␤ induces A␤ form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, A␤ exposure increases levels of nicotinic acetylcholine receptor (nAChR) ␣7 subunit protein on the cell surface and ␣7-nAChR function, but not ␣7 subunit mRNA, suggesting post-translational upregulation of functional ␣7-nAChRs. These effects are prevented upon coexposure to brefeldin A, an inhibitor of endoplasmic reticulum-to-Golgi protein transport, consistent with an effect on trafficking of ␣7 subunits and assembled ␣7-nAChRs to the cell surface. A␤ exposure-induced ␣7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an ␣7-nAChR antagonist or genetic deletion of nAChR ␣7 subunits prevents induction and expression of neuronal hyperexcitation. Collectively, these results, confirmed in studies using slice cultures, indicate that functional activity and perhaps functional upregulation of ␣7-nAChRs are necessary for production of A␤-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving ␣7-nAChRs in mediation of A␤ effects provides potentially new therapeutic targets for treatment of AD.

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“…In hippocampal pyramidal neurons, the Kv4.2 subunit is highly expressed in dendrites,17, 18 and its activity can be downregulated through phosphorylation by extracelluar‐regulated kinase, protein kinase A and C 14, 18, 19. By contrast, CaMKII‐mediated phosphorylation of Kv4.2 and Shal , the Drosophila homolog of mammalian Kv4, increases I A densities 19, 20…”

Section: Introductionmentioning

confidence: 99%

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Akita

Aoto

Kato

et al. 2018

Ann Clin Transl Neurol

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Objective α (CAMK2A) and β (CAMK2B) isoforms of Calcium/calmodulin‐dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α‐ and β‐CaMKII variants in neurodevelopmental disorders.MethodsWhole‐exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis.ResultsWe identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in‐frame deletion of the regulatory segment of CaMKII α. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro‐2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A‐type K+ currents, which facilitated spike repolarization of single action potentials.InterpretationOur data highlight the importance of CaMKII α and CaMKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A‐type K+ currents as a possible pathophysiological basis.

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Inactivity-induced increase in nAChRs upregulates Shal K+ channels to stabilize synaptic potentials

Cited by 31 publications

References 50 publications

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic

Regulation of synaptic development and function by the Drosophila PDZ protein Dyschronic

A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

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