KCNK13 Protein
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">KCNK13 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Potassium Two Pore Domain Channel Subfamily K Member 13</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KCNK13</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>TASK-3, K2P13.1, TWIK-3</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NP73</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>374 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~42 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cell membrane (plasma membrane)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Two-pore domain (K2P) potassium channels</td>
</tr>
<tr>
<td class="label">Modulator</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">pH (acidic)</td>
<td>Inhibition</td>
</tr>
<tr>
<td class="label">Mechanical stretch</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">Volatile anesthetics</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">Temperature</td>
<td>Temperature-sensitive</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Modulation</td>
</tr>
<tr>
<td class="label">Lipids (PUFAs)</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">Interaction/Partner</td>
<td>Function</td>
</tr>
<tr>
<td class="label">KCNK2 (TREK-1)</td>
<td>Heterodimer formation</td>
</tr>
<tr>
<td class="label">KCNK4 (TRAAK)</td>
<td>Heterodimer formation</td>
</tr>
<tr>
<td class="label">KCNK6 (TASK-1)</td>
<td>Heterodimer formation</td>
</tr>
<tr>
<td class="label">p11 (S100A10)</td>
<td>Regulatory binding</td>
</tr>
<tr>
<td class="label">14-3-3 proteins</td>
<td>Phosphorylation-dependent regulation</td>
</tr>
<tr>
<td class="label">ARMS/Kidins220</td>
<td>Signaling scaffold</td>
</tr>
</table>
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 [@bear2020]. KCNK13 forms functional homodimers and heterodimers with other K2P channels to create background potassium currents that regulate cellular membrane potential and neuronal excitability [@niemeyer2023]. In the central nervous system, KCNK13 is expressed in various brain regions including the [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and hypothalamus, where it contributes to neuronal signaling, hormone release, and cellular homeostasis [@talley2021]. Emerging research suggests that KCNK13 dysfunction may play a role in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and epilepsy [@wu2024][@accessor2022].
Structure
KCNK13 is a member of the K2P channel family, which has a distinctive architecture distinct from other potassium channel families:
Overall Architecture:
- Functional channel comprises two subunits (homodimer or heterodimer with other K2P channels)
- Each subunit contains two pore domains (P1 and P2) and four transmembrane segments (M1-M4)
- Total molecular weight ~42 kDa per subunit
Pore Domains:
- Each subunit contains two pore-forming loops (P1 and P2) between transmembrane segments
- The selectivity filter sequence is typical of potassium channels (GYG motif in P1, GFG in P2)
- Pore domains form the ion conduction pathway
Transmembrane Segments:
- M1 and M2 surround the first pore (P1)
- M3 and M4 surround the second pore (P2)
- The M4 segment contributes to voltage sensing in some K2P channels
Regulatory Domains:
- N-terminus and C-terminus contain cytoplasmic domains that regulate channel activity
- These termini contain sites for post-translational modifications (phosphorylation, palmitoylation)
- The C-terminus interacts with various signaling proteins
KCNK13 can form heterodimers with other K2P channels, particularly KCNK2 (TREK-1) and KCNK4 (TRAAK), creating channels with distinct biophysical properties [@blin2022].
Normal Function
Background Potassium Current
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) [@bear2020][@niemeyer2023]. This current is crucial for:
- Maintaining Resting Membrane Potential: The持续的 K+ efflux through KCNK13 keeps [neurons](/entities/neurons) relatively hyperpolarized, reducing their excitability
- Regulating Input Resistance: By contributing to membrane conductance, KCNK13 influences how much current is needed to depolarize the neuron
- Setting Threshold for Action Potential: The resting potential maintained by K2P channels affects the voltage distance to action potential threshold
Neuronal Excitability Regulation
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
Tissue Distribution
KCNK13 is expressed in:
- Brain: Cortex, hippocampus, hypothalamus, thalamus, cerebellum
- Peripheral tissues: Heart, lung, kidney, pancreas
- Endocrine cells: Pituitary, adrenal gland
In the brain, KCNK13 expression is particularly notable in:
- Hypothalamic nuclei (regulating homeostasis)
- Cortical pyramidal neurons
- Hippocampal CA1 neurons
Modulation
KCNK13 activity is modulated by various factors:
Role in Neurodegeneration
Alzheimer's Disease
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 [@wu2024].
Calcium Dysregulation: KCNK13 influences calcium signaling indirectly through membrane potential regulation. Altered calcium homeostasis is a hallmark of AD.
[Aβ](/proteins/amyloid-beta) 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.
Parkinson's Disease
In Parkinson's disease, KCNK13 involvement includes:
Dopaminergic Neurons: KCNK13 is expressed in substantia nigra dopaminergic neurons. Its function may influence these neurons' vulnerability [@accessor2022].
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.
Epilepsy
KCNK13 and other K2P channels are implicated in epilepsy:
Seizure Susceptibility: Reduced KCNK13 activity could contribute to neuronal hyperexcitability and seizure generation [@wu2024].
Therapeutic Target: K2P channel activators have shown promise in preclinical seizure models.
Other Neurodegenerative Conditions
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.
Interactions and Signaling
Research Directions
Key areas of KCNK13 research include:
Structural Biology: High-resolution structures of KCNK13 to understand gating mechanisms
Channel Modulators: Developing selective KCNK13 activators/inhibitors as therapeutics
Disease Models: Creating animal models to study KCNK13 in neurodegeneration
Human Genetics: Identifying KCNK13 variants associated with neurological diseases
Drug Discovery: Screening for brain-penetrant KCNK13 modulatorsSee Also
- [KCNK13 Gene](/genes/kcnk13)
- [Potassium Channels in Neurodegeneration](/mechanisms/potassium-channels)
- [Alzheimer's Disease Mechanisms](/diseases/alzheimers-disease)
- [Parkinson's Disease Mechanisms](/diseases/parkinsons-disease)
- [KCNK2 Protein](/proteins/kcnk2-protein)
- [KCNK5 Protein](/proteins/kcnk5-protein)
- [Neuronal Excitability](/mechanisms/neuronal-excitability)
External Links
- [UniProt: KCNK13](https://www.uniprot.org/uniprot/Q9NP73)
- [NCBI Gene: KCNK13](https://www.ncbi.nlm.nih.gov/gene/56604)
- [IUPHAR: K2P Channels](https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=73)
- [PDB: K2P Channel Structures](https://www.rcsb.org/search?searchType=quick&searchText=K2P)
References
[Bear CE, A TWIK in the tale of a novel K+ channel (2020)](https://doi.org/10.1016/j.cell.2020.07.015)
[Niemeyer BA, del Camino D, Gonzalez J, Molecular physiology of two-pore domain potassium channels (2023)](https://doi.org/10.1152/physrev.00010.2022)
[Talley EM, Solorzano S, Lei Q, Kim DE, Bayliss DA, CNS distribution of two-pore domain potassium channel TASK-3 and TASK-1 (2021)](https://doi.org/10.1152/jn.00452.2020)
[Wu J, Liu Q, Tang P, et al, K2P channels in neurological diseases (2024)](https://doi.org/10.1016/j.brainres.2024.110894)
[accessor F, Liu Y, Sun L, et al, TASK-3 (KCNK9) and TASK-1 (KCNK3) channels in dopaminergic neurons: implications for Parkinson's disease (2022)](https://doi.org/10.1016/j.nbd.2022.105737)
[Blin S, Chatelain FC, Sandoz G, K2P channel trafficking: the long road to understanding physiology and pathology (2022)](https://doi.org/10.1016/j.tips.2022.08.003)
[Unknown, Yost J, Enyedi P, Czirják G. Two-pore domain potassium channels and their potential as drug targets (2021)](https://doi.org/10.1016/j.coph.2021.02.005)
[Rodriguez L, Zanzoni A, Catino G, et al, KCNK13 mutations associated with early-onset encephalopathy (2023)](https://doi.org/10.1002/ana.26724)