Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice

Wang, Kang; Kelley, Melissa H.; Wu, Wendy; Adelman, John P.; Maylie, James

doi:10.1371/journal.pone.0139332

Cited by 9 publications

(11 citation statements)

References 22 publications

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“…Therefore, splicing may act as a molecular switch to alter the KChIP complement to regulate Kv channel function. Putative Ca 2ϩ -sensitive KChIPs in the hippocampus have been shown to respond to voltage-gated Ca 2ϩ entry within a Kv4.2-Cav2.3 microdomain to regulate the size of excitatory postsynaptic potentials (52,53). Further study is required to determine whether the Ca 2ϩ -mediated changes in Kv4 channel density observed in this study regulate dendritic excitability and/or plasticity in hippocampal pyramidal neurons.…”

Section: Ca 2؉ Regulation Of Kchip-kv4 Complexes In Hippocampal Dendrmentioning

confidence: 84%

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

Murphy

Hoffman

2019

Journal of Biological Chemistry

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Edited by Roger J. ColbranThe Kv4 family of A-type voltage-gated K ؉ channels regulates the excitability in hippocampal pyramidal neuron dendrites and are key determinants of dendritic integration, spike timing-dependent plasticity, long-term potentiation, and learning. Kv4.2 channel expression is down-regulated following hippocampal seizures and in epilepsy, suggesting A-type currents as therapeutic targets. In addition to pore-forming Kv4 subunits, modulatory auxiliary subunits called K ؉ channel-interacting proteins (KChIPs) modulate Kv4 expression and activity and are required to recapitulate native hippocampal A-type currents in heterologous expression systems. KChIP mRNAs contain multiple start sites and alternative exons that generate considerable N-terminal variation and functional diversity in shaping Kv4 currents. As members of the EF-hand domain-containing neuronal Ca 2؉ sensor protein family, KChIP auxiliary proteins may convey Ca 2؉ sensitivity upon Kv4 channels; however, to what degree intracellular Ca 2؉ regulates KChIP-Kv4.2 complexes is unclear. To answer this question, we expressed KChIP2 with Kv4.2 in HEK293T cells, and, with whole-cell patch-clamp electrophysiology, measured an ϳ1.5-fold increase in Kv4.2 current density in the presence of elevated intracellular Ca 2؉ . Intriguingly, the Ca 2؉ regulation of Kv4 current was specific to KChIP2b and KChIP2c splice isoforms that lack a putative polybasic domain that is present in longer KChIP2a1 and KChIP2a isoforms. Site-directed acidification of the basic residues within the polybasic motif of KChIP2a1 rescued Ca 2؉ -mediated regulation of Kv4 current density. These results support divergent Ca 2؉ regulation of Kv4 channels mediated by alternative splicing of KChIP2 isoforms. They suggest that distinct KChIP-Kv4 interactions may differentially control excitability and function of hippocampal dendrites.

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Section: Ca 2؉ Regulation Of Kchip-kv4 Complexes In Hippocampal Dendrmentioning

confidence: 84%

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

Murphy

Hoffman

2019

Journal of Biological Chemistry

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“…Another acute effect of VGCCs on synaptic potentials was demonstrated in CA1 pyramidal cells, where R-Type Ca 2+ channels specifically interact with K + channels. Ca 2+ influx from R-type channels activates K + channels, which results in a dampening of the EPSP, with conflicting results regarding the identity of the target K + channel (Bloodgood and Sabatini, 2007 ; Giessel and Sabatini, 2011 ; Wang et al, 2014 , 2015 ). Based on this hypothesis, we used a KMeSO3 intra to enhance the impact of Ca 2+ activated K + channels, which are reduced by K + -gluconate based intracellular solutions (Velumian et al, 1997 ).…”

Section: Resultsmentioning

confidence: 99%

“…The absence of a T- and R-type VGCC block mediated effect on synaptic depolarization measured at the soma is also relevant with respect to another interaction between VGCCs and EPSPs: in CA1 pyramidal cells, R-type VGCCs initiate a negative feedback loop by activating Ca 2+ activated K + channels. This decreases the EPSP amplitude in single spines (Bloodgood and Sabatini, 2007 ; Giessel and Sabatini, 2011 ; Wang et al, 2014 , 2015 ). In layer 5 prefrontal cortex neurons, compound EPSPs are dampened by this negative feedback loop, whereas single spine uEPSPs are not affected (Seong et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…In a number of experimental studies, the contribution of VGCCs to synaptic depolarization during EPSPs has been described as marginal (Bloodgood and Sabatini, 2007 ; Palmer and Stuart, 2009 ; Popovic et al, 2015 ). In CA1 pyramidal neurons, they are part of a negative feedback loop that dampens synaptic EPSPs (Bloodgood and Sabatini, 2007 ; Giessel and Sabatini, 2011 ; Wang et al, 2014 , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

Theis

Rózsa

Katona

et al. 2018

Front. Cell. Neurosci.

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The majority of excitatory synapses are located on dendritic spines of cortical glutamatergic neurons. In spines, compartmentalized Ca2+ signals transduce electrical activity into specific long-term biochemical and structural changes. Action potentials (APs) propagate back into the dendritic tree and activate voltage gated Ca2+ channels (VGCCs). For spines, this global mode of spine Ca2+ signaling is a direct biochemical feedback of suprathreshold neuronal activity. We previously demonstrated that backpropagating action potentials (bAPs) result in long-term enhancement of spine VGCCs. This activity-dependent VGCC plasticity results in a large interspine variability of VGCC Ca2+ influx. Here, we investigate how spine VGCCs affect glutamatergic synaptic transmission. We combined electrophysiology, two-photon Ca2+ imaging and two-photon glutamate uncaging in acute brain slices from rats. T- and R-type VGCCs were the dominant depolarization-associated Ca2+conductances in dendritic spines of excitatory layer 2 neurons and do not affect synaptic excitatory postsynaptic potentials (EPSPs) measured at the soma. Using two-photon glutamate uncaging, we compared the properties of glutamatergic synapses of single spines that express different levels of VGCCs. While VGCCs contributed to EPSP mediated Ca2+ influx, the amount of EPSP mediated Ca2+ influx is not determined by spine VGCC expression. On a longer timescale, the activation of VGCCs by bAP bursts results in downregulation of spine NMDAR function.

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“…Therefore, the size of the synaptic current measured at the cell soma is not only the result of transmitter release and glutamate receptor function but also of active membrane properties. Kv4.2 and Cav2.3 channels are localized to CA1 spines and dendrites where they affect the synaptic potential and shape its propagation (5,50,51,55,(78)(79)(80). We have previously shown that IA reduces the magnitude of spontaneous miniature EPSCs (81).…”

Section: Cav23 Channels Promote Ia-mediated Excitatory Synaptic Filtmentioning

confidence: 99%

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

Murphy

Gutzmann

Lin

et al. 2020

Preprint

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15The transient voltage-gated K + current (IA) mediated by Kv4.2 in CA1 hippocampal pyramidal 16 neurons regulates dendritic excitability, synaptic plasticity, and learning. Here we report that Ca 2+ 17 entry mediated by the voltage-gated Ca 2+ channel subunit Cav2.3 regulates Kv4.2 function in CA1 18 pyramidal neurons through Ca 2+ binding auxiliary subunits known as K + channel interacting 19 proteins (KChIPs). We characterized an interaction between Cav2.3 and Kv4.2 using 20 immunofluorescence colocalization, coimmunoprecipitation, electron microscopy, FRAP, and 21 FRET. We found that Ca 2+ -entry via Cav2.3 increases Kv4.2-mediated whole-cell current due in 22 part to an increase in Kv4.2 surface expression. In hippocampal neurons, pharmacological block 23 of Cav2.3 reduced whole-cell IA. We also found reduced IA in Cav2.3 knockout mouse neurons 24 with a loss of the dendritic IA gradient. Furthermore, the Cav2.3-Kv4.2 complex was found to 25 regulate the size of synaptic currents and spine Ca 2+ transients. These results reveal an 26 intermolecular Cav2.3-Kv4.2 complex impacting synaptic integration in CA1 hippocampal 27 neurons. 28 29 30 31 32 33 34 93 and Kv4.2 that regulates Kv4.2 function by a novel mechanism. 94 95 96 97 98 99 100 101 4 RESULTS 102 103 Cav2.3 and Kv4.2 form an ion channel complex in hippocampal neurons 104The characteristic kinetics of neuronal IA requires expression of KChIP and DPP 105 accessory subunits that had been identified and described nearly two decades ago (27, 28). In 106 an effort to identify novel Kv4.2 protein interactions and modifying enzymes in hippocampal 107 neurons we used tandem affinity purification (TAP) and protein identification with mass 108 spectrometry (MS) (58). As expected, Kv4.2 pulled down Kv4.1, Kv4.2, Kv4.3, and previously 109 described auxiliary subunits (DPPs and KChIPs) confirming the specificity of the assay (Figure 1110 -Figure supplement 1A). In addition to known binding partners, we also identified peptides 111 representing a significant proportion of the Cav2.3 amino acid sequence (Figure 1 -Figure 112 supplement 1B,C). Cav2.3 was the only voltage-gated Ca 2+ channel identified in this screen.113 To confirm the presence of a hippocampal Cav2.3 and Kv4.2 molecular complex we 114 carried out several immunological measurements using hippocampal tissue. Broad neuropil 115 colocalization of endogenous Cav2.3 and Kv4.2 immunofluorescent signal was consistent with 116 enrichment in the dendrite layers of the hippocampus as has been previously reported for each 117 channel separately (Figure 1A) (51, 59). Both Cav2.3 and Kv4.2 are also known to be expressed 118 in dendrites and spines. To evaluate Cav2.3-Kv4.2 colocalization, we transfected cultured 119 hippocampal neurons with Cav2.3-GFP (i), Kv4.2-myc (ii), and mCherry (iii) plasmids (Figure 1B). 120In addition to immunofluorescent colocalization in dendrites, both channels were enriched in 121 spines when compared to the free cytosolic mCherry fluorescent protein (Figure 1C,D). 122Immunofluorescent...

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Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice

Cited by 9 publications

References 22 publications

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

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Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice

Cited by 9 publications

References 22 publications

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels

Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

R-type voltage-gated Ca2+channels mediate A-type K+current regulation of synaptic input in hippocampal dendrites

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R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites