Kcnk13-KO Mouse

Kcnk13, also known as THIK-1, codes for a potassium (K⁺) ion channel that is part of the two-pore potassium channel family. This channel plays essential roles in maintaining the resting membrane potential and ion homeostasis. It is involved in multiple biological processes such as microglial immune surveillance, cytokine release, and has connections to the NLRP3-inflammasome pathway [4,5]. Kcnk13 is specifically expressed in human microglia, and its elevated expression has been observed in post-mortem human brain tissue from patients with Alzheimer's disease [2].

In rats, knockdown of Kcnk13 using siRNA via a recording micropipette reduced ethanol-induced excitation of ventral tegmental area (VTA) neurons, and real-time PCR showed that its expression was altered in a time-dependent manner after alcohol withdrawal. In mice, knockdown of Kcnk13 with shRNA led to a selective reduction in ethanol-induced excitation of VTA neurons and increased alcohol drinking, suggesting that ethanol may stimulate VTA neurons by inhibiting KCNK13 [1,3].

In conclusion, Kcnk13 is crucial for the regulation of neuronal activity in the VTA, especially in the context of ethanol-induced excitation, and may play a role in the development of alcohol-related disorders. In addition, its up-regulation in Alzheimer's disease indicates a potential role in neurodegenerative diseases, highlighting the importance of Kcnk13-related research in understanding these disease mechanisms [1,3,5].

References:

1. You, Chang, Vandegrift, Bertha J, Brodie, Mark S. 2021. KCNK13 potassium channels in the ventral tegmental area of rats are important for excitation of ventral tegmental area neurons by ethanol. In Alcoholism, clinical and experimental research, 45, 1348-1358. doi:10.1111/acer.14630. https://pubmed.ncbi.nlm.nih.gov/33960499/

2. Bürli, Roland W, Doyle, Kevin J, Dickson, Louise, Carlton, Mark, Dawson, Lee A. 2024. Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment. In ACS medicinal chemistry letters, 15, 646-652. doi:10.1021/acsmedchemlett.4c00035. https://pubmed.ncbi.nlm.nih.gov/38746889/

3. You, Chang, Savarese, Antonia, Vandegrift, Bertha J, Lasek, Amy W, Brodie, Mark S. 2018. Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge-like drinking. In Neuropharmacology, 144, 29-36. doi:10.1016/j.neuropharm.2018.10.008. https://pubmed.ncbi.nlm.nih.gov/30332606/

4. Madry, Christian, Kyrargyri, Vasiliki, Arancibia-Cárcamo, I Lorena, Bryan, Robert M, Attwell, David. 2017. Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1. In Neuron, 97, 299-312.e6. doi:10.1016/j.neuron.2017.12.002. https://pubmed.ncbi.nlm.nih.gov/29290552/

5. Tang, Hao, Sun, Yuhong, Fachim, Helene A, Reynolds, Gavin P, Harte, Michael K. . Elevated Expression of Two Pore Potassium Channel THIK-1 in Alzheimer's Disease: An Inflammatory Mechanism. In Journal of Alzheimer's disease : JAD, 95, 1757-1769. doi:10.3233/JAD-230616. https://pubmed.ncbi.nlm.nih.gov/37718820/