Sodium-activated potassium channel subfamily T member 1 (KCNT1)

Sodium-activated potassium channel subfamily T member 1 (KCNT1), also known as Slack, is a protein that forms a potassium channel activated by high concentrations of intracellular sodium ions [UniProt: Q5JUK3]. It is widely expressed in the central nervous system, where it regulates neuronal excitability and the rate of action potential firing by contributing to the slow afterhyperpolarization phase [NCBI Gene: 375033]. KCNT1 is a major therapeutic target because gain-of-function mutations in its gene are the primary cause of several severe, early-onset epileptic encephalopathies, such as epilepsy of infancy with migrating focal seizures (EIMFS) [PMID: 23086396]. These mutations result in increased potassium current, which paradoxically leads to neuronal hyperexcitability through complex network mechanisms. Pharmacological intervention typically involves the use of channel blockers to normalize this activity. While the anti-arrhythmic drug quinidine has been used off-label as a precision therapy for KCNT1-mutant patients, its clinical efficacy is variable and limited by systemic side effects like QT prolongation [PMID: 30703318]. Consequently, drug development efforts are currently focused on creating highly selective small-molecule inhibitors and genetic therapies to target KCNT1 more safely and effectively.

Other names

SlackKCa4.1Slo2.2KNT1EIEE14ENFL5Potassium channel subfamily T member 1

Inhibition of the potassium channel pore to reduce the excessive potassium conductance caused by gain-of-function mutations [PMID: 24535463].