Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ4
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38): 22:38,426,327-38,455,199 (from NCBI)
The KCNJ4 gene encodes a small-conductance inward rectifier potassium channel that is found in heart and brain (Perier et al., 1994; Makhina et al., 1994).
Both Perier et al. (1994) and Makhina et al. (1994) cloned and sequenced the human KCNJ4 gene. Perier et al. (1994) isolated clones for KCNJ4 (which they referred to as hippocampal inward rectifier, or HIR) from a hippocampal cDNA library using as a probe an expressed sequence tag (EST) with sequence similarity to other inward-rectifying channels such as ROMK1 (KCNJ1; 600359). They compared the primary structure of the HIR protein to other similar K+ channels. HIR was distinguished from other inwardly rectifying K+ channels by its small unitary conductance. Makhina et al. (1994) also identified the human KCNJ4 gene using the same EST probe; they referred to the channel as HRK1. The predicted 445-amino acid HRK1 protein is substantially different from the other reported inward rectifiers and may represent a new subfamily.
Budarf et al. (1995), who referred to the KCNJ4 gene as HIR, assigned the gene to chromosome 22 by PCR analysis of somatic cell hybrid DNAs. Southern blot analysis was used to sublocalize the HIR gene, using a subset of a somatic cell hybrid panel that divided the long arm of chromosome 22 into 25 regions. This procedure assigned the HIR gene to a subregion of 22q13.1. Fluorescence in situ hybridization likewise mapped the HIR gene to 22q13.1. The locus was also positioned by identifying a CEPH YAC positive for the HIR gene and identifying markers carried by that YAC.
Perier et al. (1994) studied the electrophysiological characteristics of HIR in a Xenopus oocyte expression system.
Makhina et al. (1994) found that, when expressed in Xenopus oocytes, HRK1 produced large inward K+ currents but little outward K+ current, as observed in glial cells. They proposed that HRK1 may be a predicted glial cell inward rectifier.
A complex made up of the PDZ proteins LIN7 (see LIN7A, 603380) and CASK (300172) coordinates polarized expression of KCNJ4 at renal basolateral membranes via a PDZ interaction. Using yeast 2-hybrid and coimmunoprecipitation analyses, Alewine et al. (2006) found that TIP1 (TAX1BP3; 616484) interacted directly with KCNJ4 and inhibited its interaction with LIN7/CASK, resulting in internalization and endosomal targeting of KCNJ4 in polarized rat and canine kidney cells. The interaction required the PDZ domains of TIP1 and KCNJ4. Alewine et al. (2006) proposed that TIP1 functions as a dominant-negative PDZ domain to counter the targeting of PDZ-interacting protein targets, such as KCNJ4, to basolateral membranes.
Several different potassium (K+) channels are known to be involved with electrical signaling in the nervous system. One class is activated by depolarization, whereas a second class is not. The latter are referred to as inwardly rectifying K+ channels. Inward rectifiers are a specialized class of potassium channels that produce large inward currents at potentials negative to the potassium equilibrium potential and only small outward currents at more positive potentials. This asymmetry in potassium ion conductance plays a key role in the excitability of muscle cells and neurons. Budarf et al. (1995) stated that the central role of inward rectifiers in cardiac and neuronal function suggests they may be involved in the etiology of human cardiovascular and neurologic diseases. Makhina et al. (1994) observed that, unlike the voltage regulated K+ channels which have 6 transmembrane domains, the inwardly rectifying K+ channels have only 2 membrane-spanning domains within each subunit and lack a region thought to serve as a voltage sensor in the voltage-gated channels.
Alewine, C., Olsen, O., Wade, J. B., Welling, P. A. TIP-1 has PDZ scaffold antagonist activity. Molec. Biol. Cell 17: 4200-4211, 2006. [PubMed: 16855024] [Full Text: https://doi.org/10.1091/mbc.e06-02-0129]
Budarf, M. L., Perier, F., Barnoski, B. L., Bell, C. J., Vandenberg, C. A. Assignment of the human hippocampal inward rectifier potassium channel (HIR) gene to 22q13.1. Genomics 26: 625-629, 1995. [PubMed: 7607694] [Full Text: https://doi.org/10.1016/0888-7543(95)80189-s]
Makhina, E. N., Kelly, A. J., Lopatin, A. N., Mercer, R. W., Nichols, C. G. Cloning and expression of a novel human brain inward rectifier potassium channel. J. Biol. Chem. 269: 20468-20474, 1994. [PubMed: 8051145]
Perier, F., Radeke, C. M., Vandenberg, C. A. Primary structure and characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc. Nat. Acad. Sci. 91: 6240-6244, 1994. [PubMed: 8016146] [Full Text: https://doi.org/10.1073/pnas.91.13.6240]