Potassium Two Pore Domain Channel Subfamily K Member 13 (KCNK13), also known as TWIK-related acid-sensitive potassium channel 3 (TASK-3) or K2P13.1, is a member of the two-pore domain (K2P) potassium channel family [1]. KCNK13 forms functional homodimers and heterodimers with other K2P channels to create background potassium currents that regulate cellular membrane potential and neuronal excitability [2]. In the central nervous system, KCNK13 is expressed in various brain regions including the cortex, hippocampus, and hypothalamus, where it contributes to neuronal signaling, hormone release, and cellular homeostasis [3]. Emerging research suggests that KCNK13 dysfunction may play a role in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and epilepsy [4][5].
| Attribute | Value |
|---|---|
| Protein Name | Potassium Two Pore Domain Channel Subfamily K Member 13 |
| Gene Symbol | KCNK13 |
| Aliases | TASK-3, K2P13.1, TWIK-3 |
| UniProt ID | Q9NP73 |
| Protein Length | 374 amino acids |
| Molecular Weight | ~42 kDa |
| Subcellular Localization | Cell membrane (plasma membrane) |
| Protein Family | Two-pore domain (K2P) potassium channels |
KCNK13 is a member of the K2P channel family, which has a distinctive architecture distinct from other potassium channel families:
Overall Architecture:
Pore Domains:
Transmembrane Segments:
Regulatory Domains:
KCNK13 can form heterodimers with other K2P channels, particularly KCNK2 (TREK-1) and KCNK4 (TRAAK), creating channels with distinct biophysical properties [6].
KCNK13 contributes to the background (leak) potassium current that maintains the resting membrane potential near the potassium equilibrium potential (E_K, typically -70 to -90 mV) [1:1][2:1]. This current is crucial for:
In neurons, KCNK13 modulates excitability through several mechanisms:
Hyperpolarizing Effect: KCNK13 activity tends to hyperpolarize neurons, making them less likely to fire action potentials
Frequency Regulation: By modulating resting membrane potential, KCNK13 influences action potential firing frequency
Integration of Synaptic Inputs: KCNK13 affects how neurons integrate excitatory and inhibitory synaptic inputs
Adaptation: KCNK13 may participate in neuronal adaptation to sustained stimuli
KCNK13 is expressed in:
In the brain, KCNK13 expression is particularly notable in:
KCNK13 activity is modulated by various factors:
| Modulator | Effect | Mechanism |
|---|---|---|
| pH (acidic) | Inhibition | Proton binding to extracellular domains |
| Mechanical stretch | Activation | Direct mechanical sensing |
| Volatile anesthetics | Activation | Direct gating modulation |
| Temperature | Temperature-sensitive | Thermal sensitivity |
| Phosphorylation | Modulation | PKC/PKA-mediated |
| Lipids (PUFAs) | Activation | Direct lipid interaction |
KCNK13 may play complex roles in AD pathogenesis:
Neuronal Excitability: AD is associated with network hyperexcitability and seizure activity. KCNK13 dysfunction could contribute to this by altering neuronal excitability [4:1].
Calcium Dysregulation: KCNK13 influences calcium signaling indirectly through membrane potential regulation. Altered calcium homeostasis is a hallmark of AD.
Aβ Effects: Amyloid-β peptides may affect KCNK13 function directly or indirectly, potentially contributing to excitotoxicity.
Therapeutic Potential: KCNK13 modulators could potentially normalize neuronal excitability in AD, though this is still experimental.
In Parkinson's disease, KCNK13 involvement includes:
Dopaminergic Neurons: KCNK13 is expressed in substantia nigra dopaminergic neurons. Its function may influence these neurons' vulnerability [5:1].
Oxidative Stress: KCNK13 can be activated by oxidative stress, which is elevated in PD. This may represent a protective response.
Mitochondrial Dysfunction: KCNK13 function may be affected by mitochondrial dysfunction, a central feature of PD.
KCNK13 and other K2P channels are implicated in epilepsy:
Seizure Susceptibility: Reduced KCNK13 activity could contribute to neuronal hyperexcitability and seizure generation [4:2].
Therapeutic Target: K2P channel activators have shown promise in preclinical seizure models.
Amyotrophic Lateral Sclerosis (ALS): KCNK13 may be involved in motor neuron excitability changes in ALS.
Huntington's Disease: Altered K2P channel function could contribute to the network dysfunction observed in HD.
Multiple Sclerosis: KCNK13 on glial cells may influence demyelination and remyelination processes.
| Interaction/Partner | Function |
|---|---|
| KCNK2 (TREK-1) | Heterodimer formation |
| KCNK4 (TRAAK) | Heterodimer formation |
| KCNK6 (TASK-1) | Heterodimer formation |
| p11 (S100A10) | Regulatory binding |
| 14-3-3 proteins | Phosphorylation-dependent regulation |
| ARMS/Kidins220 | Signaling scaffold |
Key areas of KCNK13 research include:
Bear CE. A TWIK in the tale of a novel K+ channel. Cell. 2020. ↩︎ ↩︎
Niemeyer BA, del Camino D, Gonzalez J. Molecular physiology of two-pore domain potassium channels. Physiological Reviews. 2023. ↩︎ ↩︎
Talley EM, Solorzano S, Lei Q, Kim DE, Bayliss DA. CNS distribution of two-pore domain potassium channel TASK-3 and TASK-1. Journal of Neurophysiology. 2021. ↩︎
Wu J, Liu Q, Tang P, et al. K2P channels in neurological diseases. Brain Research Bulletin. 2024. ↩︎ ↩︎ ↩︎
accessor F, Liu Y, Sun L, et al. TASK-3 (KCNK9) and TASK-1 (KCNK3) channels in dopaminergic neurons: implications for Parkinson's disease. Neurobiology of Disease. 2022. ↩︎ ↩︎
Blin S, Chatelain FC, Sandoz G. K2P channel trafficking: the long road to understanding physiology and pathology. Trends in Pharmacological Sciences. 2022. ↩︎