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Potassium voltage-gated channel subfamily C member 2 (KCNC2) (Kv3.2)

Target
Kv3.2
Molecular classification
Ion channel, Voltage-gated potassium channel, Kv3 (Shaw-related) subfamily
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Overview

Potassium voltage-gated channel subfamily C member 2 (Kv3.2) is a member of the Shaw-related subfamily of voltage-gated potassium channels, primarily expressed in the central nervous system, particularly in fast-spiking GABAergic interneurons (UniProt: P22456). It is characterized by its unique fast activation and deactivation kinetics at depolarized membrane potentials, which allow neurons to fire action potentials at high frequencies with minimal refractory periods (PubMed: 24639524). Kv3.2 plays a critical role in maintaining the temporal precision of neuronal signaling and regulating the release of neurotransmitters within inhibitory circuits. Dysregulation or de novo mutations in the KCNC2 gene encoding Kv3.2 are linked to various neurological disorders, including developmental and epileptic encephalopathy and cognitive deficits associated with schizophrenia (PubMed: 35145144). Pharmacological targeting of Kv3.2, often through positive allosteric modulators like AUT00206, is being explored as a therapeutic strategy to restore normal firing patterns in neuropsychiatric and neurodevelopmental conditions (ClinicalTrials.gov: NCT03280056).

Other names
KCNC2Voltage-gated potassium channel subunit Kv3.2KV3.2KSHIIIAVoltage-gated potassium channel, Shaw-related subfamily, member 2
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Mechanism of action

Positive allosteric modulation (PAM) to increase the open probability and shift the voltage-dependence of activation to more negative potentials, or non-selective inhibition of potassium efflux (PubMed: 28416633, 24639524).

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Biological functions

Action potential repolarizationHigh-frequency neuronal firingRegulation of GABAergic neurotransmissionMaintenance of neural circuit synchronyRegulation of neurotransmitter release
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Disease associations

Developmental and epileptic encephalopathy (DEE)SchizophreniaBipolar disorderCognitive impairmentPhotosensitive epilepsyGeneralized epilepsy
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Safety considerations

Risk of seizure induction due to excessive neuronal excitability modulationPotential off-target effects on other Kv3 subunits (Kv3.1, Kv3.3)CNS-related adverse effects such as dizziness, ataxia, or tremorsPotential for cardiac repolarization interference at high concentrations
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Interacting drugs

AUT00063

3 more in the full profile.

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Biomarkers

KCNC2 genetic variants (pathogenic mutations)Quantitative EEG (qEEG) signatures of fast-spiking interneuron activityMismatch negativity (MMN) in schizophrenia models

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