KCNK18 Membrane Protein Introduction

Introduction of KCNK18

KCNK18, the full name is potassium channel subfamily K member 18, also known as TWIK-related individual potassium channel, TWIK-related spinal cord potassium channel. KCNK18 is a member of the two-hole potassium (K2P) channel family, which includes 15 related pathways in humans. These channels produce a background K⁺ leakage current that controls the resting membrane potential. The KCNK18 protein is thought to form homodimers similar to other K2P channels. Each subunit contains four transmembrane domains (TMDs) and two pore-forming domains. The extracellular domain between TMD1 and TMD2 contains a conserved cysteine residue that can form a disulfide bond to aid channel dimerization and a conserved N-linked glycosylation site for surface expression of the channel. KCNK18 is unique in the K2P channel with a large intracellular regulatory domain located between TMD2 and TMD3. This domain contains two serine residues that are phosphorylated by kinases to down-regulate channel activity and are dephosphorylated by calcineurin in response to intracellular Ca²⁺ elevation, thereby activating channels. KCNK18 is highest in the dorsal root ganglia (DRG) and trigeminal ganglion (TG), both of which are important in pain. KCNK18 is also expressed in several autonomic nervous system ganglia (e.g., stellate ganglia and paraspinal sympathetic ganglia).

Function of KCNK18 Membrane Protein

The physiological role of KCNK18 currents is to inhibit cellular excitability in inflammatory responses when histamine or other inflammatory response modulators are released into the surrounding tissue. It has been established that KCNK18 is associated with migraine symptoms. The highly specific expression pattern of KCNK18 in TG neurons and the hypothesis of attenuating neuronal excitability under inflammatory conditions make it an excellent target for the development of migraine treatment.

Fig.1 KCNK18 structure predicted by utilizing PDB ID 3UKM. (Sehgal, 2014)

Application of KCNK18 Membrane Protein in Literature

1. Rainero I., et al. KCNK18 (TRESK) genetic variants in Italian patients with migraine. Headache. 2014, 54(9):1515-22. PubMed ID: 25324165
   
   

   The study showed the presence of several KCNK18 gene mutations in both migraines with aura and migraine without aura.

2. Guo Z., et al. Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. J Neurophysiol. 2014, 112(3):568-79. PubMed ID: 24805079
   
   

   The mutant TRESK subunit exerted a dominant negative effect on whole-cell TRESK currents and led to hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache.

3. Sánchez-Miguel D.S., et al. TRESK potassium channel in human T lymphoblasts. Biochem Biophys Res Commun. 2013, 434(2):273-9. PubMed ID: 23541583
   
   

   The presence of KCNK18 mRNA was confirmed in the T lymphoblastoid cell and T cell lymphoblastic leukemias/lymphomas but not in resting peripheral blood lymphocytes of healthy donors. It was discussed that the TRESK channel may be involved in lymphocyte proliferation and tumorigenesis.

4. Lafrenière R.G., et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med. 2010, 16(10):1157-60. PubMed ID: 20871611
   
   

   These results supported the role of TRESK in the pathogenesis of a typical migraine with aura and further supported the role of this channel as a potential therapeutic target.

5. Czirják G., et.al. The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J Biol Chem. 2004, 279(18):18550-8. PubMed ID: 14981085
   
   

   The TRESK channel regulated the excitability of neuronal and other cell types in response to Ca(2+)-mobilization hormones, and neurotransmitters sensitive to immunosuppressive drugs.

KCNK18 Preparation Options

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During the past years, Creative Biolabs has successfully generated many functional membrane proteins for our global customers. We are happy to accelerate the development of our clients’ programs with our one-stop, custom-oriented service. For more detailed information, please feel free to contact us.

Reference

1. Sehgal S A, et al. (2014). Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18. Drug Des Devel Ther. 8:571-81.

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