Cloning, structure and assignment to chromosome 19q13 of the human Kir2.4 inwardly rectifying potassium channel gene (KCNJ14)

Inwardly rectifying K super(+) (Kir) channels are assembled from four subunits, each consisting of two transmembrane segments flanking a pore loop region. According to sequence similarity and functional properties, 15 differentially distributed subunits are now grouped into six subfamilies (Kir1, Kir2, Kir3, Kir5, Kir6, and Kir7). Kir channels have evolved to serve diverse cellular functions such as K super(+) homeostasis, setting the membrane resting potential, modulation of neuronal firing rates, controlling pacemaker activity in the heart, as well as tuning metabolite-dependent insulin/hormone secretion. Their crucial cellular function is illustrated by mutated genes associated with inheritable diseases; for example, familial persistent hyperinsulinemic hypoglycemia or hyperprostaglandin E syndrome. Constitutively active Kir channels with strong rectification are probably formed by homomeric assembly of Kir2.1, Kir2.2, Kir2.3, and Kir2.4 subunits, which are present in the mammalian brain, heart, skeletal muscle, endothelial cells, and cellular components of the immune system. Kir2.4 is unique in its expression pattern in the rat brain. It is restricted to the large motoneurons in the spinal cord and all motor nuclei associated with cranial nerves 3-7 and 9-12, thus being the first example of an ion channel associated with a functional system. Its distinct distribution pattern renders Kir2.4 a potential candidate to be involved in the pathology of motoneuron diseases such as amyotrophic lateral sclerosis or spinal muscular atrophy. To characterize the human Kir2.4 ortholog (hKir2.4), we screened the GenBank expressed sequence tag- (EST-) database with the rat Kir2.4 (http://www.ncbi.nlm.nih.gov/blast/blast.cgi). All identified EST clones (GenBank Accession No. W25800 and I.M.A.G.E. clones 839696, 1837089, 1523087; kindly supplied by the RessourcenZentrum/PrimaerDatenbank, Berlin) lacked the majority of the 5' ORF. EST clones W25800 and 839696 were isolated from human retina cDNA libraries, suggesting that Kir2.4 subunits are also expressed in retinal neurons.