The KCC3 cotransporter as a therapeutic target for peripheral neuropathy

Delpire, Eric; Kahle, Kristopher T.

doi:10.1080/14728222.2017.1275569

Cited by 13 publications

(7 citation statements)

References 21 publications

(32 reference statements)

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“…In summary, in this work, we investigated the efficacy of KEECs to rescue a number of well-documented cellular and behavior phenotypes of RTT, including impaired GABA functional switch, reductions in excitatory synapse number and strength, immature neuronal morphology (53,54), as well as an increase in breathing pauses and a decrease in locomotion (84). It is possible, however, that KEECs may also be effective in treatment of conditions other than RTT, as impairment in KCC2 expression has been linked to many brain diseases (17,85) including epilepsy (86)(87)(88), schizophrenia (19,20,89), brain and spinal cord injury (21,90), stroke and ammonia toxicity conditions (91)(92)(93), as well as the impairments in learning and memory observed in the senile brain (23). Thus, a phenotypically diverse array of brain diseases may benefit from enhancing the expression of KCC2.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

et al. 2019

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K+/Cl− cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT. To develop neuron-based high-throughput screening (HTS) assays to identify chemical compounds that enhance the expression of the KCC2 gene, we report the generation of a robust high-throughput drug screening platform that allows for the rapid assessment of KCC2 gene expression in genome-edited human reporter neurons. From an unbiased screen of more than 900 small-molecule chemicals, we have identified a group of compounds that enhance KCC2 expression termed KCC2 expression–enhancing compounds (KEECs). The identified KEECs include U.S. Food and Drug Administration–approved drugs that are inhibitors of the fms-like tyrosine kinase 3 (FLT3) or glycogen synthase kinase 3β (GSK3β) pathways and activators of the sirtuin 1 (SIRT1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) pathways. Treatment with hit compounds increased KCC2 expression in human wild-type (WT) and isogenic MECP2 mutant RTT neurons, and rescued electrophysiological and morphological abnormalities of RTT neurons. Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

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Section: Discussionmentioning

confidence: 99%

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

et al. 2019

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“…KCC2 and KCC3 are important therapeutic targets in the case of peripheral neuropathy (29), epilepsy (30), and acute central nervous injury (31). The widely-applied diuretics furosemide and bumetanide favors NKCCs than KCCs (32).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for regulation of human potassium chloride cotransporters

Chi

Chen

et al. 2020

Preprint

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The Solute Carrier Family 12 (SLC12) encodes electroneutral cation-chloride cotransporters (CCCs) that are fundamental in cell volume regulation and chloride homeostasis. Dysfunction of CCCs engenders abnormality in renal function and neuro-system development. Here we presented structure of the full length human potassium-chloride co-transporter 2 (KCC2) and 3 (KCC3), the KCC3 mutants in phosphorylation mimic (P-mimic) and dephosphorylation mimic (DP-mimic) status, and KCC3 in complex with [(DihydroIndenyl)Oxy] Alkanoic acid (DIOA), a specific inhibitor of KCCs, at resolution of 2.7 Å -3.6 Å. A small N-terminal loop is bound at the intracellular vestibule of the transport path, arresting the transporter in an autoinhibition state. The C-terminal domain (CTD) of KCCs is structure-solved for the first time, revealing two conserved phosphorylation harboring segments (PHSs), which exhibit different conformation between P-mimic and DP-mimic mutants, explaining the inhibitory effect of phosphorylation. DIOA is located in between the two transmembrane domains, tightly bound to the loop between TM10 and TM11, locking the transporter in inward-facing conformation. Together, our study makes important steps in understanding the sophisticated regulation mechanisms of KCCs, with prospect for the specific drug development.

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“…This is the first description of a mutation in a transporter that has an effect on ECM. Previous studies have shown that pharmacological activation of KCC channels is achievable 40,41 , therefore future research into KCC1 activation may provide novel treatments for cerebral malaria.…”

Section: Discussionmentioning

confidence: 99%

KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria

Hortle

Starrs

Brown

et al. 2019

Sci Rep

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Plasmodium falciparum malaria causes half a million deaths per year, with up to 9% of this mortality caused by cerebral malaria (CM). One of the major processes contributing to the development of CM is an excess of host inflammatory cytokines. Recently K+ signaling has emerged as an important mediator of the inflammatory response to infection; we therefore investigated whether mice carrying an ENU induced activation of the electroneutral K+ channel KCC1 had an altered response to Plasmodium berghei . Here we show that Kcc1 M935K/M935K mice are protected from the development of experimental cerebral malaria, and that this protection is associated with an increased CD4+ and TNFa response. This is the first description of a K+ channel affecting the development of experimental cerebral malaria.

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The KCC3 cotransporter as a therapeutic target for peripheral neuropathy

Cited by 13 publications

References 21 publications

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Molecular basis for regulation of human potassium chloride cotransporters

KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria

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