M-current preservation contributes to anticonvulsant effects of valproic acid

Kay, Hee Yeon; Greene, Derek L.; Kang, Seungwoo; Kosenko, Anastasia; Hoshi, Naoto

doi:10.1172/jci79727

Cited by 42 publications

(43 citation statements)

References 53 publications

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“…Synaptic protein palmitoylation is also affected by seizures and anticonvulsants (18,55,56), and several DHHC PAT mutations and substrates have been linked to neurological and neuropsychiatric disorders, including Huntington's, schizophrenia, and X-linked intellectual disability, that are characterized by altered synaptic plasticity (48,57,58). Our findings here reveal novel cross-talk between postsynaptic Ca 2ϩ signaling, palmitoylation, and phosphorylation pathways that are required for synaptic plasticity and thus have implications for understanding these diseases.…”

Section: Camkii Regulates Akap79/150 Function In Ltdmentioning

confidence: 69%

CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

Woolfrey¹,

O’Leary²,

Goodell

et al. 2018

Journal of Biological Chemistry

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/CaM, a mechanism that favors phosphorylation by prolonged, weak LTD stimuli versus brief, strong LTP stimuli. Phosphorylation by CaMKII inhibited AKAP79/150 association with F-actin; it also facilitated AKAP79/150 removal from spines but was not required for it. By contrast, LTD-induced spine removal of AKAP79/150 required its depalmitoylation on two Cys residues within the N-terminal targeting domain. Notably, such LTD-induced depalmitoylation was also blocked by CaMKII inhibition. These results provide a mechanism how CaMKII can indeed mediate not only LTP but also LTD through regulated substrate selection; however, in the case of AKAP79/150, indirect CaMKII effects on palmitoylation are more important than the effects of direct phosphorylation. Additionally, our results provide the first direct evidence for a function of the well-described AKAP79/150 trafficking in regulating LTD-induced spine shrinkage. LTP7 and LTD are two opposing forms of synaptic plasticity that together are thought to underlie learning, memory, and cognition (1, 2). CaMKII and its Ca 2ϩ -independent autonomous kinase activity that is generated by Thr-286 autophosphorylation have been tightly linked to LTP for over 25 years (3-6); by contrast, an additional requirement in LTD is just emerging (7,8). LTD also requires the phosphatase calcineurin (CaN) (9, 10), and specifically a pool of CaN co-anchored with protein kinase A (PKA) at synapses by AKAP79 (in humans) or AKAP150 (the rodent homologue) (11-13). However, somewhat paradoxically, LTD stimuli ultimately trigger the synaptic removal of , suggesting the following model: LTD stimuli quickly induce CaN-dependent dephosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at the PKA site Ser-845 to promote AMPAR internalization; subsequent CaN-dependent AKAP79/150 removal then removes AKAP-anchored PKA from synapses to prevent GluA1 Ser-845 re-phosphorylation (12,15). Here, we show that synaptic AKAP79/150 removal is also required for structural LTD (i.e. the shrinkage of dendritic spines) and that this removal requires CaMKII. Thus, our results provide a direct mechanistic explanation for the requirement of CaMKII in LTD as well as the first direct evidence for a requirement of the well-studied AKAP79/150 removal from spines in an LTD mechanism.

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Section: Camkii Regulates Akap79/150 Function In Ltdmentioning

confidence: 69%

CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

Woolfrey¹,

O’Leary²,

Goodell

et al. 2018

Journal of Biological Chemistry

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“…As an extreme example, retigabine-induced augmentation of the M-current has seen great success as an antiepileptic therapy [167], and more recently it was determined that one of the predominant antiepileptic drugs, valproic acid, owes part of its protective activity to the preservation of the M-current during seizures [168]. In contrast, removal of Kv7.2 increases susceptibility to seizures and leads to deficits in hippocampal-dependent spatial memory [124] as well as fear memory in mice [169].…”

Section: Resultsmentioning

confidence: 99%

Modulation of Kv7 channels and excitability in the brain

Greene

Hoshi

2016

Cell. Mol. Life Sci.

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142

144

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Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.

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“…Signals were sampled at 2 kHz, filtered at 1 kHz, and acquired using pClamp software (version 10; Molecular Devices). The perforated patch‐clamp method with amphotericin B was used to record macroscopic currents as described previously . Briefly, patch pipettes (1‐2 MΩ) were filled with the intracellular solution containing 130 mmol/L potassium acetate, 15 mmol/L KCl, 3 mmol/L MgCl 2 , 6 mmol/L NaCl, 10 mmol/L 4‐(2‐hydroxyethyl)‐1‐piperazineethanesulfonic acid (HEPES) (adjusted to pH = 7.2 by NaOH), and amphotericin B (0.1‐0.2 mg/mL).…”

Section: Methodsmentioning

confidence: 99%

“…After establishing stable current recording for more than 2 minutes, 0.3 μmol/L oxo‐M was applied for 2 minutes, followed by 10 μmol/L XE991 to assess M‐current suppression as well as achieve complete inhibition of the M‐current. For SCG neurons, deactivating currents during −50 mV step hyperpolarization were measured as the M‐current as described . The dose‐response curve was fit using an equation I = 1 − (1 − I min )/(1 + (IC 50 /[oxo‐M])), where I min is the resistant fraction of the M‐current, IC 50 is the half inhibition concentration, and [oxo‐M] is the concentration of oxo‐M.…”

Section: Methodsmentioning

confidence: 99%

“…When this key PKC phospho‐acceptor serine residue in the Kv7.2 subunit is mutated to alanine, neurotransmitter‐induced M‐current suppression is drastically attenuated . We recently demonstrated that valproate (VPA) treatment disrupts M‐current suppression and observed that resultant preserved M‐current contributes to the anticonvulsant action of VPA …”

Section: Introductionmentioning

confidence: 99%

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Attenuating M‐current suppression in vivo by a mutant Kcnq2 gene knock‐in reduces seizure burden and prevents status epilepticus–induced neuronal death and epileptogenesis

2018

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This study provides evidence that neurotransmitter-induced suppression of M-current generated by Kv7.2-containing channels exacerbates behavioral seizures. In addition, prompt recovery of M-current after status epilepticus prevents subsequent neuronal death and the development of spontaneously recurrent seizures. Therefore, prompt restoration of M-current activity may have a therapeutic benefit for epilepsy.

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M-current preservation contributes to anticonvulsant effects of valproic acid

Cited by 42 publications

References 53 publications

CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

Modulation of Kv7 channels and excitability in the brain

Attenuating M‐current suppression in vivo by a mutant Kcnq2 gene knock‐in reduces seizure burden and prevents status epilepticus–induced neuronal death and epileptogenesis

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