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PubMed1996

Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome.

The KCNE1 gene encodes a small protein, IsK, of 14.4 kDa, with a single transmembrane domain, and is part of a potassium channel expressed in the heart. This channel is thought to underly the very slow component of the cardiac delayed rectifying current which controls the duration and the degree of ventricular repolarization. This suggested that KCNE1 could be the morbid gene responsible for an autosomal recessive cardio-auditory disease, the Jervell and Lange-Nielsen syndrome, characterized by ventricular repolarization abnormalities and recurrent syncopes leading eventually to sudden death associated with a bilateral congenital deafness. By linkage analysis in four consmanguinous families, using microsatellite markers of chromosome 21 as well as KCNE1 intragenic polymorphisms, we excluded KCNE1 as a candidate gene for Jervell and Lange-Nielsen syndrome. In addition, we described a new polymorphism, a G-to-A substitution at position 253, in the KCNE1 coding sequence detectable by SSCP analysis or RFLP.

Female↗

PubMed1997

A new inward rectifier potassium channel gene (KCNJ15) localized on chromosome 21 in the Down syndrome chromosome region 1 (DCR1).

The Down syndrome chromosome region-1 (DCR1) on subband q22.2 of chromosome 21 is thought to contain genes contributing to many features of the trisomy 21 phenotype, including dysmorphic features, hypotonia, and psychomotor delay. Isolation, mapping, and sequencing of trapped exons and captured cDNAs from cosmids of this region have revealed the presence of a gene (KCNJ15) encoding a potassium (K+) channel belonging to the family of inward rectifier K+ (Kir) channels. The amino acid sequence deduced from the 1125-bp open reading frame indicates that this gene is a member of the Kir4 subfamily; it has been named Kir4.2. It is expressed in kidney and lung during human development and in several adult tissues including kidney and brain. After Kir3.2 (GIRK2), Kir4.2 is the second K+ channel gene of this type described within the DCR1.

Adult↗

PubMed2002

[Effect of angiotensin II on potassium channels of ischemic ventricular myocytes of the guinea pig].

The experiments were carried out on guinea pig isolated ventricular myocytes by using whole-cell patch clamp. The effects of angiotensin II (Ang II) on potassium ion channels of acute ischemic myocytes were observed. Whole-cell patch clamp recordings showed that physiological potassium current, including delayed rectifier potassium current and inward rectifier potassium current were inhibited under the condition of simulated ischemia, and then further inhibited by treatment with Ang II. ATP-sensitive potassium currents were increased under simulated ischemia and were further enhanced by Ang II treatment.

Angiotensin II↗

PubMed1994

Hybrid potassium channels by tandem linkage of inactivating and non-inactivating subunits.

We constructed tandem cDNA by linking the 5' end of a delayed rectifier-type (Kv1.2) clone to the 3' end of a transient-type (Kv1.4) K+ channel clone. Fusion genes were also constructed, consisting of Kv1.4 and mutants of Kv1.2, which have a single amino acid substitution in the S4-S5 loop. From electrophysiological characterization, it is likely that two pairs of tandem heterodimer constructs can form hybrid channels. In addition, it has been revealed that the wild-type hybrid channel shows a time constant of inactivation very similar to that observed in the homotetrameric Kv1.4 channel. Difference of inactivation kinetics between wild-type and mutant hybrid K+ channels suggests that not only the S4-S5 loop of Kv1.4 but also that of Kv1.2 can serve as the acceptor sites for the inactivation gates, and that all of four sets of loops should be functional for rapid inactivation. From these results, in the hybrid channels the structure and composition of the acceptor sites could be important factors for determining the rate of inactivation.

Amino Acid Sequence↗

PubMed1990

Two types of delayed rectifying K+ channels in atrial cells of guinea pig heart.

Whole-cell clamp experiments revealed the double exponential deactivation of the delayed rectifier K+ current in single guinea pig atrial myocytes. Two types of K(+)-selective channels were identified by applying repolarizing voltage pulses to cell-free patches from atrial cell membrane, where inward-rectifier, ATP-sensitive, and muscarinic K+ channels were all inactivated. Under a symmetrical 150 mM K+ condition, single channel conductances of the channels were 10 and 3 pS. The reversal potential obtained from the unitary current-voltage relation coincided with the equilibrium potential for K+. Ensemble averages of both types of single channel currents showed deactivation kinetics upon hyperpolarizing to potentials between -40 and -120 mV. The more positive the pre-pulse potential, the greater was the peak ensemble current. It is concluded that these two channels are responsible for atrial delayed rectifying K+ currents.

Animals↗

PubMed1997

A minK-HERG complex regulates the cardiac potassium current I(Kr).

MinK is a widely expressed protein of relative molecular mass approximately 15K that forms potassium channels by aggregation with other membrane proteins. MinK governs ion channel activation, regulation by second messengers, and the function and structure of the ion conduction pathway. Association of minK with a channel protein known as KvLQT1 produces a voltage-gated outward K+ current (I[sK]) resembling the slow cardiac repolarization current (I[Ks]). HERG, a human homologue of the ether-a-go-go gene of the fruitfly Drosophila melanogaster, encodes a protein that produces the rapidly activating cardiac delayed rectifier (I[Kr]). These two potassium currents, I(Ks) and I(Kr), provide the principal repolarizing currents in cardiac myocytes for the termination of action potentials. Although heterologously expressed HERG channels are largely indistinguishable from native cardiac I(Kr), a role for minK in this current is suggested by the diminished I(Kr) in an atrial tumour line subjected to minK antisense suppression. Here we show that HERG and minK form a stable complex, and that this heteromultimerization regulates I(Kr) activity. MinK, through the formation of heteromeric channel complexes, is thus central to the control of the heart rate and rhythm.

Animals↗

PubMed1989

Permeation, selectivity, and blockade of the Ca2+-activated potassium channel of the guinea pig taenia coli myocyte.

The permeation properties of the 147-pS Ca2+-activated K+ channel of the taenia coli myocytes are similar to those of the delayed rectifier channel in other excitable membranes. It has a selectivity sequence of K+ 1.0 greater than Rb+ 0.65 greater than NH4+ 0.50. Na+, Cs+, Li+, and TEA+ (tetraethylammonium) are impermeant. Internal Na+ blocks K+ channel in a strongly voltage-dependent manner with an equivalent valence (zd) of 1.20. Blockade by internal Cs+ and TEA+ is less voltage dependent, with d of 0.61 and 0.13, and half-blockage concentrations of 88 and 31 mM, respectively. External TEA+ is about 100 times more effective in blocking the K+ channel. All these findings suggest that the 147-pS Ca2+-activated K+ channel in the taenia myocytes, which functions physiologically like the delayed rectifier, is the single-channel basis of the repolarizing current in an action potential.

Ammonia↗

PubMed2006

The delayed rectifier channel current IK plays a key role in the control of programmed cell death by PACAP and ethanol in cerebellar granule neurons.

Alcohol exposure during development causes severe brain malformations, and thus, identification of molecules that can counteract the neurotoxicity of ethanol deserves high priority. Since activation of potassium (K+) currents has been shown to play a critical role in the control of programmed cell death, we have investigated the effects of ethanol and PACAP on K+ currents in cultured cerebellar granule cells using the patch-clamp technique in the whole cell configuration. In the presence of the fast-inactivating IA current blocker 4-AP, a focal application of ethanol (200 mM) in the vicinity of granule cells provoked a robust hyperpolarization and a marked increase of the delayed rectifier IK current. Addition of PACAP (0.1 microM) in the bath solution prevented ethanol-induced membrane hyperpolarization and suppressed the stimulatory effect of ethanol on IK current. These data suggest that ethanol alters neuronal survival, at least in part, through activation of IK, and that PACAP abolishes ethanol-induced cerebellar granule cell death via inhibition of IK..

Apoptosis↗

PubMed1997

Diversity of response in vascular smooth muscle cells to changes in oxygen tension.

Hypoxia causes pulmonary vasoconstriction (HPV), but also dilation of systemic vessels and the ductus arteriosus. In the adult animal. HPV is initiated by inhibition of potassium current (IK) in the smooth muscle cells of small resistance arteries, which results in membrane depolarization and calcium entry through voltage-gated calcium channels. The oxygen-sensitive channels that initiate HPV are 4-aminopyridine (4-AP)-sensitive delayed rectifier channels (KDR), the most prominent of which has a conductance of 37 pS. In the fetus, hypoxia causes pulmonary vasoconstriction through inhibition of a calcium-sensitive potassium channel (KCa). In smooth muscle cells from the rabbit ductus arteriosus, which dilates in response to hypoxia, whole-cell potassium current is reversibly enhanced, rather than inhibited, by hypoxia. The principal oxygen-sensitive channel is inhibited by 4-AP and has a conductance of about 58 pS. There are morphological and electrophysiological differences between individual pulmonary artery smooth muscle cells, for example, in some cells IK is predominantly carried by KDR channels and in others by KCa channels. KDR cells are more common in the resistance pulmonary arteries and KCa in the conduit arteries. Responses of specific vessels (conduit, resistance; pulmonary, systemic, ductus) at different stages of development (fetal, neonatal and adult) to changes in oxygen tension may be determined by the distribution of a variety of ion channels in the smooth muscle cells.

Animals↗

PubMed1990

Identification of electrophysiologically distinct subpopulations of rat taste cells.

The gustatory sensory system provides animals with a rapid chemical analysis of a potential food substance providing information necessary to facilitate ingestion or rejection of the food. The process of gustatory transduction is initiated in the taste cells in the lingual epithelium. However, due to the small size, scarcity of the cells and their location, embedded in a keratinized squamous epithelium, it has been difficult to study the primary events in the transduction process. Recently, we have developed a preparation of dissociated rat taste cells that permits studies of the taste transduction process in single isolated cells. We have now investigated the electrophysiological properties of the rat taste cells using the patch-clamp technique. We have identified two populations of cells within the taste bud: one expressing a voltage-dependent potassium current and the second containing both voltage-dependent sodium and potassium currents. The potassium current in both cell groups is blocked by external TEA, Ba2+, and quinine. Two types of K+ channels have been identified: a 90-pS delayed rectifier K+ channel and a "maxi" calcium-activated K+ channel. The sodium current is blocked by TTX, but not by amiloride.

Animals↗

PubMed1997

Properties and regulation of the minK potassium channel protein.

The minK gene encodes a protein of 130 amino acids that has a single transmembrane segment and is expressed in many tissues including heart, uterus, and kidney. When Xenopus oocytes are injected with minK mRNA, a very slowly activating voltage-dependent potassium current is induced in these cells. The induced channels appear to result from the interaction of the minK protein with other channel-forming subunits such as the KvLQT1 channel. The minK protein is intimately associated with the structure of the resultant channels, and mutations in minK can alter ion selectivity and modulation by second messengers. Strong candidates for native currents regulated by the minK protein include the slow component of the cardiac delayed rectifier and potassium currents recorded across epithelial cells in vestibular organs and cochlea.

Amino Acid Sequence↗

PubMed2004

Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development.

To understand molecular mechanisms that regulate formation and maintenance of cardiac IKr (rapidly activating component of the delayed rectifier K+ current), we have investigated the spatiotemporal expression pattern of two rat potassium voltage-gated channels, namely subfamily H (eag-related), member2 (KCNH2) (alias name: rERG) and Isk-related family, member2 (KCNE2) (alias name: rMiRP1) during late embryonic development by means of the in situ hybridization technique. KCNE2 is transcribed predominantly in atrial und ventricular myocardium at stages E14.5-E18.5dpc and only a minor signal emerged in the tongue at E16.5dpc. In contrast, KCNH2 transcripts appeared in a less confined pattern with intense signals in atrial and ventricular myocardium, somites, spinal cord, bowel system, central nervous system and thymus at stages E14.5-E18.5dpc. Non-cardiac expression even exceeds the intensity of the cardiac signal, indicating that KCNH2 contributes to K+ currents in non-cardiac tissue as well. Transcription of the rat b-subunit KCNE2 is present in all regions of the fetal myocardium and co-distributes perfectly with transcription of the pore forming a-subunit KCNH2. It seems likely that KCNH2 and KCNE2 are linked to form cardiac IKr channels, associated to cardiogenesis and cardiomyocyte excitability.

Animals↗

PubMed1995

Regulation of voltage-gated ion channels by NGF and ciliary neurotrophic factor in SK-N-SH neuroblastoma cells.

Neurotrophic factors have powerful effects on neuronal differentiation and the maintenance of neuronal phenotype, but understanding of their regulation of one important aspect of neuronal function, excitability, remains limited. We have examined the regulation of voltage-gated ion channels by two unrelated neurotrophic factors, NGF and ciliary neurotrophic factor (CNTF), in the SK-N-SH neuroblastoma cell line that is responsive to both factors. NGF and CNTF have strikingly different neuronal specificities and distributions in the nervous system, and might be expected to have significantly different effects on neuronal function. Using whole-cell, perforated-patch, and single-channel recording, we found that treatment with NGF increased levels of voltage-gated sodium, calcium, and potassium currents. In contrast, CNTF treatment increased levels of potassium currents only. NGF and CNTF appeared to regulate the same delayed-rectifier potassium current; in addition, NGF treatment resulted in increased levels of a second potassium current component. Such differential effects of neurotrophic factors on the expression of voltage-gated ion channels would have profound effects on the excitability of target neurons in vivo.

Calcium↗

PubMed2001

K(+) channel profile and electrical properties of Arabidopsis root hairs.

Ion channels and solute transporters in the plasma membrane of root hairs are proposed to control nutrient uptake, osmoregulation and polar growth. Here we analyzed the molecular components of potassium transport in Arabidopsis root hairs by combining K(+)-selective electrodes, reverse transcription-PCR, and patch-clamp measurements. The two inward rectifiers AKT1 and ATKC1 as well as the outward rectifier GORK dominated the root hair K(+) channel pool. Root hairs of AKT1 and ATKC1 loss-of-function plants completely lack the K(+) uptake channel or exhibited altered properties, respectively. Upon oligochitin-elicitor treatment of root hairs, transient changes in K(+) fluxes and membrane polarization were recorded in wild-type plants, while akt1-1 root hairs showed a reduced amplitude and pronounced delay in the potassium re-uptake process. This indicates that AKT1 and ATKC1 represent essential alpha-subunits of the inward rectifier. Green fluorescent protein (GFP) fluorescence following ballistic bombardment with GORK promoter-GFP constructs as well as analysis of promoter-GUS lines identified this K(+) outward rectifier as a novel ion channel expressed in root hairs. Based on the expression profile and the electrical properties of the root hair plasma membrane we conclude that AKT1-, ATKC- and GORK-mediated potassium transport is essential for osmoregulation and repolarization of the membrane potential in response to elicitors.

Acetylglucosamine↗

PubMed1993

Functional and biochemical characterization of the human potassium channel Kv1.5 with a transplanted carboxyl-terminal epitope in stable mammalian cell lines.

The role of the C-terminal domain of the hPCN1/Kv1.5 delayed rectifier K+ channel was investigated in transfected stable cell lines employing antipeptide and anti-epitope antibodies against hPCN1-cp, an epitope-fusion gene carrying additional sequences encoding a 32 amino acid C-terminal extension. Both wild-type and chimeric genes showed high levels of K+ channel expression. Detailed electrophysiologic characterization showed there to be no significant effect of the C-terminal extension on channel activity. Immunoblots of whole-cell and membrane preparations demonstrated primarily intact protein in which the C-terminal extension was not cleaved from the peptide chain. Two bands were visualized from cells transfected with either the wild-type or chimeric channels; the slower migrating band was a non-N-glycosylated form. The epitope-fusion method will be a useful adjunct to studying the role of functional domains in ion channels, and may provide a means for rapid affinity purification of channel protein.

Amino Acid Sequence↗

PubMed2000

Isolation and heterologous expression of two genomic clones encoding Shaker-related potassium channels of trout CNS.

Two Shaker-related potassium channel genes (termed tsha1 and tsha2) expressed in the CNS of trout were cloned and sequenced. The coding regions of both genes were not interrupted by introns and exhibited a high overall sequence similarity to other members of the Shaker subfamily. By computer-assisted sequence alignments, tsha1 was identified as a fish homologue to the mammalian Kv1.2 subtype of potassium channels, whereas tsha2 did not show a preferential sequence homology but shared a uniform similarity to Kv1.1, Kv1.2, and Kv1.3. Upon heterologous expression in a mammalian glial cell line, both channels exhibited delayed rectifier current properties that differed from each other by their threshold potentials of activation and their pharamcological features: wheras the tsha1-mediated current was efficiently blocked by submicromolar concentrations of alpha-DTX but not by TEA, tsha2 was highly TEA-sensitive, correlating well with differences in the amino acid structure of the pore outer mouth region. As revealed by RT-PCR, Shaker-related potassium channels were sequentially expressed during trout brain development: tsha2 was found initially at stage 34, followed by tsha1 at stage 36, whereas two other members of the Shaker family (tsha3 and tsha4) were detectable much earlier (stage 30, hatching). In the mature brain tissue, no regional specialization of Shaker channel subtype expression was noted.

Amino Acid Sequence↗

PubMed1998

Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion.

An early sign of human myoblast commitment to fusion is the expression of a non-inactivating delayed rectifier K+ current, I(K(NI)), and an associated membrane potential hyperpolarization. We have isolated the full-length coding region of a human ether-a-go-go K+ channel (h-eag) from myoblasts undergoing differentiation. The h-eag gene was localized to chromosome 1q32-41, and is expressed as a approximately 9 kb transcript in myogenic cells and in adult brain tissue. Forced expression of h-eag in undifferentiated myoblasts generates a current with remarkable similarity to I(K(NI)) indicating that h-eag constitutes the channel responsible for this current in vivo.

Adolescent↗

PubMed2000

Dispersion of ventricular repolarization and ventricular fibrillation in left ventricular hypertrophy: influence of selective potassium channel blockers.

This study tested the hypothesis that combination ion channel blockers of the transient outward current (I(to)) and the rapid component of the delayed rectifying current (I(Kr)) would produce greater prolongation of the ventricular action potential duration (APD) and increased dispersion of the APD in hypertrophied hearts compared with control hearts. Isolated rabbit hearts were studied 48 +/- 5 days postabdominal aortic banding. Left ventricular endocardial and epicardial APDs were significantly greater at baseline in the hypertrophied group than in controls (P <.05). The magnitude of APD prolongation induced by the I(to) blocker 4-aminopyridine (4-AP) and combination 4-AP and the I(Kr) blocker dofetilide was greater in the hypertrophied hearts than in the normal hearts (P <.01). Mean APD dispersion was significantly greater in the hypertrophied group than in the control hearts at baseline (P <.05). 4-AP increased APD dispersion by a similar magnitude in the hypertrophied hearts (10 +/- 10 ms) and the control hearts (8 +/- 8 ms, P = NS), whereas the combination 4-AP and dofetilide increased APD dispersion by a greater magnitude in the hypertrophied hearts (41 +/- 28 ms) than the control hearts (21 +/- 11 ms, P <.05). Ventricular fibrillation occurred spontaneously in four hypertrophied hearts (40%) during combination drug perfusion and in none of the control hearts (P <.05). Thus, combination I(to) and I(Kr) blockers cause greater prolongation APD and increased APD dispersion in left ventricular hypertrophy, and this is associated with the development of ventricular fibrillation.

4-Aminopyridine↗