Zn2+‐induced Ca2+ release via ryanodine receptors triggers calcineurin‐dependent redistribution of cortical neuronal Kv2.1 K+ channels

Schulien, Anthony J.; Justice, Jason A.; Maio, Roberto Di; Wills, Zachary P.; Shah, Niyathi H.; Aizenman, Elias

doi:10.1113/jp272117

Cited by 18 publications

(12 citation statements)

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“…DTDP induces Zn 2+ liberation from intracellular stores (Aizenman et al, 2000), which, in turn can mediate Ca 2+ release via ryanodine receptors (Woodier et al, 2015; Schulien et al, 2016). As such, Zn 2+ , under certain circumstances, may induce calcineurin-dependent K V 2.1 declustering (Schulien et al, 2016). Interestingly, K V 2.1 clusters remained intact following a brief 10 minute treatment with 30 μM DTDP, at least for approximately 90 minutes following exposure (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

“…In neurons, this process termed preconditioning, relies on a transient increase in free Zn 2+ and activation of the Ca 2+ -dependent phosphatase calcineurin (Lockshin & Williams, 1965; Aras et al , 2009b; Schulien et al , 2016). Our laboratory previously reported that, preconditioned neurons display dispersed K V 2.1 somato-dendritic clusters (Aras et al , 2009b).…”

Section: Discussionmentioning

confidence: 99%

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Disruption of K V 2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents

Justice

Schulien

et al. 2017

Neuroscience

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As the predominant mediator of the delayed rectifier current, KV2.1 is an important regulator of neuronal excitability. KV2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of KV2.1, resulting in an augmented delayed rectifier current that acts as a conduit for K+ efflux required for pro-apoptotic protease/nuclease activation. Recent evidence suggests that KV2.1 somato-dendritic clusters regulate the formation of endoplasmic reticulum–plasma membrane junctions that function as scaffolding sites for plasma membrane trafficking of ion channels, including KV2.1. However, it is unknown whether KV2.1 somato-dendritic clusters are required for apoptogenic trafficking of KV2.1. By overexpression of a protein derived from the C-terminus of the cognate channel KV2.2 (KV2.2CT), we induced calcineurin-independent disruption of KV2.1 somato-dendritic clusters in rat cortical neurons, without altering the electrophysiological properties of the channel. We observed that KV2.2CT-expressing neurons are less susceptible to oxidative stress-induced cell death. Critically, expression of KV2.2CT effectively blocked the increased current density of the delayed rectifier current associated with oxidative injury, supporting a vital role of KV2.1-somato-dendritic clusters in apoptogenic increases in KV2.1-mediated currents.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disruption of K V 2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents

Justice

Schulien

et al. 2017

Neuroscience

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“…We note that the clustering of Kv2.1 is conditional in many if not all of these cell backgrounds, such that it occurs in M-phase but not interphase COS-1 cells (47), polarized MDCK cells in confluent epithelial monolayers but not in nonpolarized MDCK cells in low density culture (35), and in PC12 cells before but not after differentiation with nerve growth factor (102). Moreover, in neurons and HEK293 cells, changes in protein kinase (54, 99) and protein phosphatase (39, 52, 53, 80, 103, 104) activity leads to changes in Kv2.1 phosphorylation state and clustering, and presumably its association with ER-PM junctions. As such, the mechanism whereby Kv2.1 organizes ER-PM junctions may involve regulation via dynamic changes in phosphorylation state, including in critical serine residues within the PRC domain itself (37, 47).…”

Section: Discussionmentioning

confidence: 99%

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

Kirmiz

Palacio

Thapa

et al. 2018

Preprint

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27Endoplasmic reticulum (ER) and plasma membrane (PM) form junctions crucial to ion and lipid 28 signaling and homeostasis. The Kv2.1 ion channel is unique among PM proteins in organizing 29 ER-PM junctions. Here, we show that this organizing function is conserved between Kv2 family 30 members that differ in their biophysical properties, modulation and cellular expression. 31Manipulation of actin cytoskeleton surrounding Kv2 ER-PM junctions affects their spatial 32 organization. Kv2-containing ER-PM junctions overlap with those formed by canonical ER-PM 33 tethers. ER-PM junction organization by Kv2 channels is unchanged by point mutations that 34 eliminate ion conduction, but abolished by those that eliminate PM clustering without impacting 35 ion channel function. Kv2.2 is distinct in lacking the reversible modulation of junction organization 36 present in Kv2.1. Brain neurons in Kv2 double knockout mice have altered ER-PM junctions, 37 demonstrating a conserved in vivo function for Kv2 family members distinct from their canonical 38 role as ion-conducting channels shaping neuronal excitability. 39 40. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 3 Introduction 41Membrane contacts between the endoplasmic reticulum (ER) and plasma membrane (PM), or 42 ER-PM junctions, are a ubiquitous feature of eukaryotic cells (1-4). These specialized sites at 43 which ER is held in close apposition (10-30 nm) and other excitable and non-excitable cell types. In brain neurons, Kv2 channels are distinct from 63 other Kv channels (17) in being specifically localized to high-density micron sized clusters 64 prominent on the soma, proximal dendrites, and axon initial segment (34-42). Kv2 channels also 65 form such clusters when exogenously expressed in cultured neurons and in heterologous cells 66 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 4 (35, 37, 39, 41-47 at/near RyR clusters in specific neuron types, including hippocampal CA1 pyramidal neurons and 114 layer 6 neocortical neurons (Figure 1). A similar juxtaposition of Kv2.2 and RyR clusters was seen 115 in CHNs (Figure 1). In these classes of neurons, Kv2.2 was often found coclustered with Kv2.1 at 116 these ER-PM junctions (Figure 1). Neurons in each preparation also contained RyR clusters that 117 did not appear to colocalize with Kv2.2 or Kv2.1 (Figure 1). These findings demonstrate that Kv2.2 118 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted ...

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“…The influx of Zn 2+ into the cell awakens the Ca 2+ related processes, which is observed not only in neurons [ 126 ], but also in other cells [ 127 ].…”

Section: Zincmentioning

confidence: 99%

General Aspects of Metal Ions as Signaling Agents in Health and Disease

et al. 2020

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This review focuses on the current knowledge on the involvement of metal ions in signaling processes within the cell, in both physiological and pathological conditions. The first section is devoted to the recent discoveries on magnesium and calcium-dependent signal transduction—the most recognized signaling agents among metals. The following sections then describe signaling pathways where zinc, copper, and iron play a key role. There are many systems in which changes in intra- and extra-cellular zinc and copper concentrations have been linked to important downstream events, especially in nervous signal transduction. Iron signaling is mostly related with its homeostasis. However, it is also involved in a recently discovered type of programmed cell death, ferroptosis. The important differences in metal ion signaling, and its disease-leading alterations, are also discussed.

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Zn²⁺‐induced Ca²⁺ release via ryanodine receptors triggers calcineurin‐dependent redistribution of cortical neuronal Kv2.1 K⁺ channels

Cited by 18 publications

References 42 publications

Disruption of K V 2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents

Disruption of K V 2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

General Aspects of Metal Ions as Signaling Agents in Health and Disease

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