Alternative titles; symbols
HGNC Approved Gene Symbol: KCNK1
Cytogenetic location: 1q42.2 Genomic coordinates (GRCh38): 1:233,614,106-233,672,514 (from NCBI)
KCNK1 is a potassium-selective, pH-sensitive, openly rectifying channel regulated by sumoylation (see SUMO1; 601912) (Rajan et al., 2005).
Lesage et al. (1996) cloned a member of a new class of potassium channels by computer identification of an EST with predicted sequence similarity to the P domain, a region involved in the potassium conduction pathway, of other channels. A cDNA, designated TWIK1 by the authors, was obtained from a human kidney library and shown to encode a predicted 336-amino acid protein. Unlike other potassium channels, TWIK1 has 4, rather than 6, transmembrane domains and 2, rather than 1, P domains. Two genes from C. elegans are related. Northern blot analysis showed that TWIK1 was widely expressed, with high levels in brain and heart.
Lesage et al. (1996) found that human TWIK1 could direct expression of weakly inward-rectifying potassium currents when expressed in Xenopus oocytes. They speculated that TWIK1 channels may be involved in the control of background potassium membrane conductances.
Rajan et al. (2005) found that K2P1 was sumoylated on intracellular lys274 by Xenopus or human UBC9 (UBE2I; 601661) at the cell surface, and that sumoylation rendered the channel inactive. Mutation of lys274 or desumoylation of K2P1 by SENP1 (612157) activated the mute pore, allowing its characterization. K2P1 functioned as a potassium-selective leak channel with unitary conductance that passed larger outward than inward currents under physiologic conditions. K2P1 was active at all physiologic voltages and was sensitive to external pH via protonation of conserved his122 in the first P loop. Rajan et al. (2005) concluded that K2P1 is an openly rectifying potassium channel that is sensitive to pH and regulated by sumoylation.
Crystal Structure
Miller and Long (2012) presented the 3.4-angstrom resolution crystal structure of a human K2P channel, K2P1 (TWIK1). Unlike other potassium channel structures, K2P1 is dimeric. An extracellular cap domain located above the selectivity filter forms an ion pathway in which potassium ions flow through side portals. Openings within the transmembrane region expose the pore to the lipid bilayer and are filled with electron density attributable to alkyl chains. An interfacial helix appears structurally poised to affect gating.
Lesage et al. (1996) mapped the KCNK1 gene by in situ hybridization to 1q42-q43.
Eigenbrod et al. (2019) found that various species of subterranean naked mole rats were insensitive to pain from 1 or more substances, including capsaicin, acid (HCl), or allyl isothiocyanate (AITC), an algogen produced by a South African stinging ant. Animals were tested with each of the 3 stimuli and RNA was isolated from sensory tissues for sequencing. Two of the acid-insensitive species had downregulated ASIC3 (ACCN3; 611741) and TWIK1 transcripts, and others showed amino acid changes in the TRPA1 (604775) channel protein. The highveld mole rat (Cryptomys hottentotus pretoriae), which was particularly insensitive to AITC, had upregulated expression of NALCN (611549). Overexpression of NALCN increases background sodium currents associated with membrane leakiness, which acts as a shunt so that injection of current cannot as easily produce membrane depolarization, and therefore dampens pain perception. Animals treated with verapamil, an NALCN blocker, responded strongly to AITC injections. Eigenbrod et al. (2019) concluded that pain insensitivity in mole rat species has been driven by a combination of selection for the ability to feed on pungent plants and, for the highveld mole rat, the ability to coexist with aggressive stinging ants.
Eigenbrod, O., Debus, K. Y., Reznick, J., Bennett, N. C., Sanchez-Carranza, O., Omerbasic, D., Hart, D. W., Barker, A. J., Zhong, W., Lutermann, H., Katandukila, J. V., Mgode, G., Park, T. J., Lewin, G. R. Rapid molecular evolution of pain insensitivity in multiple African rodents. Science 364: 852-859, 2019. [PubMed: 31147513] [Full Text: https://doi.org/10.1126/science.aau0236]
Lesage, F., Guillemare, E., Fink, M., Duprat, F., Lazdunski, M., Romey, G., Barhanin, J. TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J. 15: 1004-1011, 1996. [PubMed: 8605869]
Lesage, F., Mattei, M.-G., Fink, M., Barhanin, J., Lazdunski, M. Assignment of the human weak inward rectifier K+ channel TWIK-1 gene to chromosome 1q42-q43. Genomics 34: 153-155, 1996. [PubMed: 8661042] [Full Text: https://doi.org/10.1006/geno.1996.0259]
Miller, A. N., Long, S. B. Crystal structure of the human two-pore domain potassium channel K2P1. Science 335: 432-436, 2012. [PubMed: 22282804] [Full Text: https://doi.org/10.1126/science.1213274]
Rajan, S., Plant, L. D., Rabin, M. L., Butler, M. H., Goldstein, S. A. N. Sumoylation silences the plasma membrane leak K(+) channel K2P1. Cell 121: 37-47, 2005. Note: Erratum: Cell 141: 368 only 2010. [PubMed: 15820677] [Full Text: https://doi.org/10.1016/j.cell.2005.01.019]