Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Mahadevan, Vivek; Khademullah, C. Sahara; Dargaei, Zahra; Chevrier, Jonah; Uvarov, Pavel; Kwan, Julian; Bagshaw, Richard D.; Pawson, Tony; Emili, Andrew; Anggono, Victor; Airaksinen, Matti S.; Woodin, Melanie A.

doi:10.1101/142265

Cited by 5 publications

(6 citation statements)

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“…The second possibility is that, contrary to KCC2 E/+ monogenic model, all cited above works that studied bumetanide treatment were performed on multifactorial models involving long-lasting changes of large number of genes and signaling pathways (50,61,62) as well as reported changes of neuronal Cl − homeostasis in brain slices from juvenile [P30; (9)] or young adult [P60; (40,47)] animals. Last, the described bumetanideresistant impairment of social interaction in KCC2 E/+ mice might involve bumetanide/chloride homeostasis-independent long-lasting changes of the interaction with one of few out of multiple recently identified KCC2 partners (63).…”

Section: Discussionmentioning

confidence: 92%

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

et al. 2019

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KCC2 is a vital neuronal K+/Cl− cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007. We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.

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Section: Discussionmentioning

confidence: 92%

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

et al. 2019

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“…Moreover, 7 of these proteins (CACNA1B, GAP43, DPYSL2, DGKQ, PCLO, SNPH, and RIMS1) are highly specific for presynaptic compartments and regulate neurotransmitter release (80)(81)(82)(83)(84)(85)(86), whereas 9 proteins (AKAP5, CTNND2, EPB41L1, LPPR4, LRRC7, MARCKS, SLC12A5, SPTBN1 and SRCIN1) are abundant in postsynaptic compartments (Fig. 5C) and contribute to postsynaptic signaling (87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). In addition, EFV effects on Ca 2+ , GTPase, and catenin signaling were identified, the novel and important findings because aberrant signaling through all of these pathways is tightly linked to progression of AD (139)(140)(141)(142).…”

Section: Discussionmentioning

confidence: 99%

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov

Mast

et al. 2019

FASEB j.

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Efavirenz (EFV) is an anti‐HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid‐decreasing paradigm of CYP46A1 activation by EFV. These approaches revealed increases in the brain levels of postsynaptic density protein 95, gephyrin, synaptophysin, synapsin, glial fibrillary acidic protein, and CYP46A1 and documented altered expression and phosphorylation of 66 genes and 77 proteins, respectively. The data obtained pointed to EFV effects at the synaptic level, plasmin‐depended amyloid clearance, inflammation and microglia phenotype, oxidative stress and cellular hypoxia, autophagy and ubiquitin‐proteasome systems as well as apoptosis. These effects could be realized in part via changes in the Ca2+‐, small GTPase, and catenin signaling. A model is proposed, in which CYP46A1‐dependent lipid raft rearrangement and subsequent decrease of protein phosphorylation are central in EFV effects and explain behavioral improvements in EFV‐treated 5XFAD mice.—Petrov, A. M., Mast, N., Li, Y., Pikuleva, I. A. The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment. FASEB J. 33, 8782–8798 (2019). http://www.fasebj.org

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“…), we have previously demonstrated that changes in E GABA can be detected using whole‐cell recordings (Ormond and Woodin, , Ormond and Woodin, , Takkala and Woodin, , Mahadevan et al . ). The use of the whole‐cell technique was necessary in the present study as a result of the longer‐term nature of the recordings, which required the washing‐in and ‐out of pharmacological agents, and the need to include a pharmacological agent in the recording pipette.…”

Section: Resultsmentioning

confidence: 97%

“…KCC2 has also been shown to physically interact with several excitatory receptors and proteins (Mahadevan et al . ), including the GluK2 subunit of kainate receptors (KARs) (Mahadevan et al . ), and the KAR auxiliary subunit Neto‐2 (Ivakine et al .…”

Section: Introductionmentioning

confidence: 99%

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

Garand

Mahadevan

Woodin

2019

The Journal of Physiology

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Key points Potassium‐chloride co‐transporter 2 (KCC2) plays a critical role in regulating chloride homeostasis, which is essential for hyperpolarizing inhibition in the mature nervous system. KCC2 interacts with many proteins involved in excitatory neurotransmission, including the GluK2 subunit of the kainate receptor (KAR). We show that activation of KARs hyperpolarizes the reversal potential for GABA (EGABA) via both ionotropic and metabotropic signalling mechanisms. KCC2 is required for the metabotropic KAR‐mediated regulation of EGABA, although ionotropic KAR signalling can hyperpolarize EGABA independent of KCC2 transporter function. The KAR‐mediated hyperpolarization of EGABA is absent in the GluK1/2−/− mouse and is independent of zinc release from mossy fibre terminals. The ability of KARs to regulate KCC2 function may have implications in diseases with disrupted excitation: inhibition balance, such as epilepsy, neuropathic pain, autism spectrum disorders and Down's syndrome. Abstract Potassium‐chloride co‐transporter 2 (KCC2) plays a critical role in the regulation of chloride (Cl−) homeostasis within mature neurons. KCC2 is a secondarily active transporter that extrudes Cl− from the neuron, which maintains a low intracellular Cl− concentration [Cl−]. This results in a hyperpolarized reversal potential of GABA (EGABA), which is required for fast synaptic inhibition in the mature central nervous system. KCC2 also plays a structural role in dendritic spines and at excitatory synapses, and interacts with ‘excitatory’ proteins, including the GluK2 subunit of kainate receptors (KARs). KARs are glutamate receptors that display both ionotropic and metabotropic signalling. We show that activating KARs in the hippocampus hyperpolarizes EGABA, thus strengthening inhibition. This hyperpolarization occurs via both ionotropic and metabotropic KAR signalling in the CA3 region, whereas it is absent in the GluK1/2−/− mouse, and is independent of zinc release from mossy fibre terminals. The metabotropic signalling mechanism is dependent on KCC2, although the ionotropic signalling mechanism produces a hyperpolarization of EGABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR:KCC2 complex may play an important role in excitatory:inhibitory balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signalling can regulate inhibition via multiple mechanisms. Activation of kainate‐type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during periods of strong glutamatergic activity.

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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Abstract: 12as a novel and potent negative regulator of KCC2.

Cited by 5 publications

References 124 publications

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Abstract: 12as a novel and potent negative regulator of KCC2.

Cited by 5 publications

References 124 publications

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Ionotropic and metabotropic kainate receptor signalling regulates Cl− homeostasis and GABAergic inhibition

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Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition