KCNK4 Membrane Protein Introduction

Introduction of KCNK4

KCNK4, the full name is potassium channel subfamily K member 4, also known as TWIK-related arachidonic acid-stimulated potassium channel protein1 Publication (TRAAK1), two-pore potassium channel KT4.1. KCNK4 is K⁺-selective channel of the two-pore domain (K2P) family. It is a robustly mechanosensitive channel. The KCNK4 channel contains two protomers, each containing two different pore domains, forming a double symmetric K⁺ channel. The extracellular surface has a 35 Å tall helical cap. Whether applied by stretching, poking, swelling or fluid jet stimulation or to excised membrane patches through pressure-induced stretch, KCNK4 current can be activated. In addition to being mechanically sensitive, KCNK4 channel is also regulated by chemical and physical stimuli, including lipids, hemolytic lipids, arachidonic acid and other polyunsaturated fatty acids (PUFAs), temperature, phosphorylation, and pH. KCNK4 is a target for clinical drugs, including volatile anesthetics, antidepressants, neuroleptics, and sedatives.

Function of KCNK4 Membrane Protein

KCNK4 channel is expressed in the central and peripheral nervous systems, including in sensory neurons of the dorsal root ganglia where mechanosensitive cation nonselective channels are also expressed. KCNK4 channel can be activated by mechanical force directly through the lipid bilayer: it is membrane tension-gated channel. It opens rapidly in response to tension and has an apparently low threshold and a broad range of tension activation. Functionally, in the presence of arachidonic acid and various polyunsaturated fatty acids, KCNK4 channel activation has been demonstrated to afford potent neuroprotection against brain ischemia/hypoxia/anoxia by reducing neuronal excitability as well as cardioprotection from ischemic damage. Further neuroprotective/neuromodulatory effects of KCNK4 channel is associated with neuroepithelial O2 perception. As a possible regulator of sensory information, by modulating neuronal excitation, KCNK4 channel is also associated with neuronal and skin temperature regulation and nociception. The functional role of the KCNK4 channel has also been confirmed in the regulation of cardiac rhythm, potential spontaneous sleep apnea, and pulmonary physiology.

Fig.1 The structure of KCNK4. (Brohawn, 2015)

Application of KCNK4 Membrane Protein in Literature

1. Conway K., et al. Racial variation in breast tumor promoter methylation in the Carolina Breast Cancer Study. Cancer Epidemiol Biomarkers Prev. 2015, 24(6):921-30. PubMed ID: 25809865
   
   

   The results indicated that KCNK4 promoter methylation was associated with breast cancer.

2. Brohawn S.G., et al. Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature. 2014, 516(7529):126-30. PubMed ID: 25471887
   
   

   The results showed how to use the tension of the lipid bilayer to control the gating and mechanical sensitivity of eukaryotic TRAAK K⁺ ion channels.

3. Brohawn S.G., et al. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proc Natl Acad Sci U S A. 2014, 111(9):3614-9. PubMed ID: 24550493
   
   

   The TRAAK response was similar to the mechanical force of the ion channel Piezo1; the mechanical activation of TRAAK can electrically counter the Piezo1 activation.

4. Brohawn S.G., et al. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science. 2012, 335(6067):436-41. PubMed ID: 22282805
   
   

   They presented the crystal structure of human TRAAK at a resolution of 3.8 angstroms, explaining the insensitivity of the two-porous K(+) channel to inhibitory toxins. The two diagonally opposite gate-forming inner helical formed membrane-interacting structures that may be the basis for the sensitivity of the channel to the chemical and mechanical properties of the cell membrane.

5. Harinath S and Sikdar S.K. Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels. Neuropharmacology. 2004, 46(5):750-60. PubMed ID: 14996553
   
   

   The results identified TREK-1 and TRAAK channels as molecular targets for trichloro ethanol and suggested that activation of these channels may contribute to central nervous system (CNS) inhibition of chloral hydrate (CH).

KCNK4 Preparation Options

Membrane protein studies have advanced significantly over the past few years. Based on our versatile Magic™ membrane protein production platform, we could offer a series of membrane protein preparation services for worldwide customers in reconstitution forms or other protein forms in the same family. Aided by our versatile Magic™ anti-membrane protein antibody discovery platform, we also provide customized anti-KCNK4 antibody development services.

• Magic™ Membrane Protein Production Platform
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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. Brohawn S G. (2015). How ion channels sense mechanical force: insights from mechanosensitive K2P channels TRAAK, TREK1, and TREK2. Ann N Y Acad Sci. 1352:20-32.

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