Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and G(s), G(i), and G(q) protein-coupled receptors (original) (raw)
Related papers
KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents
Journal of Biological Chemistry, 2000
KCNQ2 and KCNQ3, both of which are mutated in a type of human neonatal epilepsy, form heteromeric potassium channels that are expressed in broad regions of the brain. The associated current may be identical to the M-current, an important regulator of neuronal excitability. We now show that the RNA encoding the novel KCNQ5 channel is also expressed in brain and in sympathetic ganglia where it overlaps largely with KCNQ2 and KCNQ3. In addition, it is expressed in skeletal muscle. KCNQ5 yields currents that activate slowly with depolarization and can form heteromeric channels with KCNQ3. Currents expressed from KCNQ5 have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. A KCNQ5 splice variant found in skeletal muscle displays altered gating kinetics. This indicates a molecular diversity of channels yielding Mtype currents and suggests a role for KCNQ5 in the regulation of neuronal excitability.
FEBS Letters, 2000
The two P domain hTRAAK K + channel has been cloned from human brain. hTRAAK cDNA encodes a 393 amino acid polypeptide with 88% of homology with its mouse counterpart. The hTRAAK gene has been mapped to chromosome 11q13 and the study of its organization indicates that the hTRAAK open reading frame is contained in six exons. hTRAAK is expressed abundantly in brain and placenta. In COS cells, hTRAAK currents are K + -selective, instantaneous and noninactivating. These currents are insensitive to the classical K + channels blockers 4-aminopyridine, tetraethylammonium, barium and quinidine, but are strongly stimulated by application of arachidonic acid as well as other polyunsaturated fatty acids. hTRAAK can also be activated by a stretch of the membrane.
Localization of Two Potassium Channel β Subunit Genes, KCNA1B and KCNA2B
Genomics, 1996
subunits may also associate with non-Shaker channels, The gating properties and current amplitudes of and additional b subunit genes may have evolved in mammalian voltage-activated Shaker potassium chanassociation with other K / channel families (15, 18). nels are modulated by at least two associated b sub-Mutations in genes encoding a subunits of K / chanunits (Kvb1.1 and Kvb1.2). The human Kvb1.1 gene nels are associated with episodic ataxia/myokymia (1) (KCNA1B) resides on chromosome 3, as indicated by and Long QT syndrome (3). Mutations in K / channel somatic cell hybrid mapping. More precise localization b subunits may also cause inherited diseases; testing of KCNA1B to 3q26.1 was obtained with fluorescence of this hypothesis would be facilitated by chromosomal in situ hybridization (FISH) and was corroborated by localization of these genes. Here, we report the map-PCR screening of the CEPH YAC library. The human ping of the human Kvb1.1 (KCNA1B) and Kvb1.2 Kvb1.2 gene (KCNA2B) resides on chromosome 1, as
MS#013 Aminoff M Nat Genet 21 309 313 1999
Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations 1,2 . At the cellular level, MGA1 is characterized by selective intestinal vitamin B 12 (B 12 , cobalamin) malabsorption 2 . MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries 3-6 and Norway 1,7 , and highest in Finland 8 (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B 12 receptor, cubilin, was recently cloned 9,10 ; the human homologue, CUBN, was mapped to the same region 10 . We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, finemapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.
Genomic Localization of the Human Gene for KCNA10, a cGMP-Activated K Channel
Genomics, 1997
been shown to be caused by defective K channels. Since Potassium (K) channels are important components the K channel superfamily is very diverse, and given of virtually all cells, and they play critical roles in that these proteins are critical components of virtually many cellular functions. KCNA10 represents a new all cells, it is likely that abnormal K channels consticlass of K channel specifically regulated by cGMP and tute the molecular basis of additional human diseases. postulated to mediate the effects of substances that The genetic and physical maps of the human genome increase intracellular cGMP. Since KCNA10 has the are continually being refined, and many inherited dispotential to be useful in candidate gene analysis of eases are now linked to small regions of specific chroinherited diseases, the human gene for KCNA10 was mosomes. In parallel studies, a large number of genes, characterized. Fluorescence in situ hybridization indiincluding K channel genes, have already been isolated, cates that human KCNA10 maps to chromosome 1 at and many can potentially be used in candidate gene p13.1 r p22.1. Finer mapping of the gene was achieved analysis. However, for cloned genes to be useful in such by PCR of a set of CEPH YAC clones that spanned the studies, one must first determine their localization on region of interest. We found that YAC 818b9 contains human chromosomes. human KCNA10. These data indicate human KCNA10 We recently identified a novel rabbit gene that enmaps to 1p13.1 and resides within the genetic interval codes a K-selective channel (rabKCNA10) selectively defined by microsatellite loci D1S2809 and D1S2726. up-regulated by cGMP (Yao et al., 1995). KCNA10 de-That region of chromosome 1 contains another K chanfines a new class of K channels with structural features nel gene, KCNA3. ᭧ 1997 Academic Press common both to voltage-gated Shaker-like K channels and to cyclic nucleotide-gated nonselective cation channels. It could play an important role in mediating the
Genomics, 1997
magnetic beads. Random-primed cDNAs were pre-The Down syndrome chromosome region-1 (DCR1) pared from poly(A) / RNAs derived from three human on subband q22.2 of chromosome 21 is thought to contissues: fetal brain, fetal liver, and adult skeletal mustain genes contributing to many features of the tricle. Tissue-specific adapters were ligated to the cDNAs somy 21 phenotype, including dysmorphic features, and amplified using Bluescript SK primers. After caphypotonia, and psychomotor delay. Isolation, mapture on solid-phase, the cDNAs were eluted, amplified, ping, and sequencing of trapped exons and captured and subcloned into UDG Cloning Vector pAMP10 (Life cDNAs from cosmids of this region have revealed the Technologies) using the manufacturer's protocol. A topresence of a gene (KCNJ15) encoding a potassium tal of 768 cDNA clones were ordered and spotted on (K / ) channel belonging to the family of inward rectifier membranes. The DNAs of the overlapping cosmids K / (Kir) channels. The amino acid sequence deduced c102D1298 and c102F0165 were digested with BamHI from the 1125-bp open reading frame indicates that and BglII for exon trapping experiments using the this gene is a member of the Kir4 subfamily; it has Gibco BRL Exon Trapping system (Life Technologies) been named Kir4.2. It is expressed in kidney and lung and the protocol provided by the manufacturer. An adduring human development and in several adult tisditional step of T 4 -ligation of the product of the UDG sues including kidney and brain. After Kir3.2 (GIRK2), cloning in pAMP10 was performed before the final elec-Kir4.2 is the second K / channel gene of this type described within the DCR1. ᭧ 1997 Academic Press
Genomics, 1993
The four Shaker-like subfamilies of Shaker-, Shab-, Shaw-, and Shal-related K + channels in mammals have been defined on the basis of their sequence homologies to the corresponding Drosophila genes. Using interspecific backcrosses between Mus musculus and Mus spretus, we have chromosomally mapped in the mouse the Shaker-related K+-channel genes Kcnal, Kcna2, Kcna4, KcnaS, and Kcna6; the Shab-related gene Kcnb l ; the Shaw-related gene Kcnc4; and the Shal-related gene Kcnd2. The following localizations were determined: Chr 2, cen-Acra-Kcna4-Pax-6-a-Pck-1-Kras-3-Kcnbl (corresponding human Chrs 11p and 20q, respectively); Chr 3, cen-Hao-2-(Kcna2, Kcnc4)-Amy-1 (human Chr 1); and Chr 6, cen-Cola-2-Met-K c n d2-Cpa-Tcrb-adr/Clc -1 -Hox-1.1 -Myk -103 -Raf-l-(Tpi-1, Kcnal, Kcna5, Kcna6) (human Chrs 7q and 12p, respectively). Thus, there is a cluster of at least three Shaker-related K+-channel genes on distal mouse Chr 6 and a cluster on Chr 2 that at least consists of one Shaker-related and one Shaw-related gene. The three other K+-channel genes are not linked to each other. The map positions of the different types of K +channel genes in the mouse are discussed in relation to those of their homologs in man and to hereditary diseases of mouse and man that might involve K + channels.
Cloning of two transcripts, HKT4.1a and HKT4.1b, from the human two-pore K+ channel gene KCNK4
Molecular Brain Research, 2002
The human KCNK4 gene encodes several transcripts that generate two-pore K channel subunits. We describe the identification and cloning of two transcripts of this gene: human KT4.1a (HKT4.1a) and HKT4.1b. They encode proteins of 393 and 419 amino acids, respectively. HKT4.1a and mouse TRAAK (mTRAAK) are 83% identical, polymerase chain reaction (PCR) experiments performed with rat and human samples as well as the comparison of the HKT4.1 and mTRAAK UTRs strongly suggest that both the human and mouse cDNAs are products of ortholog genes. In contrast to the reported exclusive expression mTRAAK in the nervous system, human and rat KCNK4 gene products are expressed widely in several tissues. Northern blot analysis revealed the presence of three bands of 1.9, 3.0, and 4.8 kb in human, while in rat four bands of 1.8, 3.6, 5.2 and 8.6 kb were observed. Human KCNK4 transcripts were expressed mainly in the heart and brain but also in the liver, skeletal muscle, kidney and pancreas. In rat, the transcripts were strongly expressed in the brain but were also detected in the lung, kidney, liver, spleen, skeletal muscle, testes and at lower levels in the heart. Expression of HKT4.1b in Xenopus oocytes drives the resting potential close to the potassium equilibrium voltage. The expressed channels are not gated by voltage 1 1 1 1 and are permanently open. The channels are not blocked by the classical K channel blockers TEA, 4-AP, Cs , Ba , quinine or quinidine. Analysis of genomic sequences reveals that seven exons participate to produce HKT4.1a and 11 exons to produce HKT4.1b cDNAs. The KCNK4 gene maps to chromosome 11q13.