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At least 19 recordsLinked to original sources
PubMed1991

L-type calcium channels, potassium channels, and novel nonspecific cation channels in a clonal muscle cell line derived from embryonic rat ventricle.

We have characterized the membrane currents in the H9c2 clonal muscle cell line derived from embryonic rat ventricle. These cells, established by selective serial passage and clonal proliferation, have been found by Hescheler and coworkers to express dihydropyridine-sensitive calcium channels that respond to beta-adrenergic stimulation. We have investigated the macroscopic and elementary currents in these cells by using standard patch-clamp methods. In cells that are kept confluent for 3-4 weeks, we have confirmed the expression of L-type calcium channels and additionally establish that the unitary conductance of many, but not all, of these channels (25 pS in 70 mM barium) is equal to that of cardiac rather than skeletal muscle. When the cells are proliferating rapidly, calcium channels are sparse or absent, but at least two distinct potassium channels and a nonspecific cation channel are observed. The nonspecific channel exhibits a conductance of 30 pS in physiological saline and conducts sodium, potassium, and calcium with nearly equal efficacy. Several unusual properties distinguish this nonspecific channel from others described previously. Gating is voltage dependent, with slow activation and marked increases in open probability at positive potentials. Unlike voltage, activation and marked increases in open probability at positive potentials. Unlike voltage, changes in [Ca2+] or in membrane stretch do not noticeably influence activity. In conclusion, our work and that of Hescheler et al indicate that H9c2 cells are potentially valuable surrogates for the investigation of ion channel regulation and muscular gene expression.

Animals↗
PubMed1990

Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone.

Resistance arteries exist in a maintained contracted state from which they can dilate or constrict depending on need. In many cases, these arteries constrict to membrane depolarization and dilate to membrane hyperpolarization and Ca-channel blockers. We discuss recent information on the regulation of arterial smooth muscle voltage-dependent Ca channels by membrane potential and vasoconstrictors and on the regulation of membrane potential and K channels by vasodilators. We show that voltage-dependent Ca channels in the steady state can be open and very sensitive to membrane potential changes in a range that occurs in resistance arteries with tone. Many synthetic and endogenous vasodilators act, at least in part, through membrane hyperpolarization caused by opening K channels. We discuss evidence that these vasodilators act on a common target, the ATP-sensitive K (KATP) channel that is inhibited by sulfonylurea drugs. We propose the following hypotheses that presently explain these findings: 1) arterial smooth muscle tone is regulated by membrane potential primarily through the voltage dependence of Ca channels; 2) many vasoconstrictors act, in part, by opening voltage-dependent Ca channels through membrane depolarization and activation by second messengers; and 3) many vasodilators work, in part, through membrane hyperpolarization caused by KATP channel activation.

Animals↗
PubMed1991

Use of toxins to study potassium channels.

Potassium channels comprise groups of diverse proteins which can be distinguished according to each member's biophysical properties. Some types of K+ channels are blocked with high affinity by specific peptidyl toxins. Three toxins, charybdotoxin, iberiotoxin, and noxiustoxin, which display a high degree of homology in their primary amino acid sequences, have been purified to homogeneity from scorpion venom. While charybdotoxin and noxiustoxin are known to inhibit more than one class of channel (i.e., several Ca(2+)-activated and voltage-dependent K+ channels), iberiotoxin appears to be a selective blocker of the high-conductance, Ca(2+)-activated K+ channel that is present in muscle and neuroendocrine tissue. A distinct class of small-conductance Ca(2+)-activated K+ channel is blocked by two other toxins, apamin and leiurotoxin-1, that share no sequence homology with each other. A family of homologous toxins, the dendrotoxins, have been purified from venom of various related species of snakes. These toxins inhibit several inactivating voltage-dependent K+ channels. Although molecular biology approaches have been employed to identify and characterize several species of voltage-gated K+ channels, toxins directed against a particular channel can still be useful in defining the physiological role of that channel in a particular tissue. In addition, for those K+ channels which are not yet successfully probed by molecular biology techniques, toxins can be used as biochemical tools with which to purify the target protein of interest.

Amino Acid Sequence↗
PubMed1992

Lack of effect of potassium channel openers on ATP-modulated potassium channels recorded from rat ventromedial hypothalamic neurones.

1. Single neuronal cells were freshly isolated from the ventromedial hypothalamic nuclei (VMHN) of the rat brain. Currents through ATP-modulated and large conductance (160 and 250 pS) calcium-activated potassium channels were recorded by the cell-attached and excised inside-out patch techniques. 2. BRL38227 (lemakalim; 30-90 microM) applied to the superfusing medium produced no change in firing rate of isolated glucose-receptive VMHN neurones in cell-attached recordings. 3. BRL38227, at concentrations of between 30-100 microM applied to the intracellular (cytoplasmic) aspect of inside-out patches, had no effect on the activity of ATP-sensitive K+ channels in the absence of ATP or in the presence of a sub-maximal inhibitory concentration (3 mM) of ATP. Cromakalim, pinacidil, minoxidil sulphate and diazoxide also produced no effect under these conditions. 4. The potassium channel openers (KCO's) were tested on ATP-activated potassium channels recorded from a further subpopulation of VMHN neurones. Application of BRL38227 (up to and including 100 microM) to this channel in inside-out patches either in the absence of ATP or when activated by 5 mM ATP had no effect on channel activity. Identical results were obtained with cromakalim and pinacidil. 5. BRL38227 had no effect on either of the large conductance (250 pS and 160 pS) calcium-activated potassium channels in VMHN neurones. 6. Intracellular recordings were made from glucose-receptive VMHN neurones in rat brain slices. Cromakalim (50 microM) or diazoxide (60 microM) did not alter the firing rate or passive membrane properties of these neurones demonstrated to be sensitive to tolbutamide (0.1 mM). 7. These results show that the KCO's tested in this study have no effect either on VMHN neurones contained in brain slices or on the activity of any of the ATP-modulated potassium channels under isolated patch conditions associated with these neurones.

Adenosine Triphosphate↗
PubMed1990

GABA-induced potassium channels in cultured neurons.

When gamma-aminobutyric acid (GABA) or baclofen were applied to cultured rat hippocampal neurons, single-channel potassium currents appeared after a delay of 30 s or more in patches of membrane on the cell surface isolated from the agonists by the recording pipette. The appearance of currents in patches not exposed to agonist, the delay in their appearance and the suppression of currents in cells pre-incubated with pertussis toxin indicate the involvement of an intracellular second messenger system. The channels were associated with a GABAB receptor rather than a GABAA receptor as they were blocked by baclofen, a GABAB antagonist, but were not affected by bicuculline, a GABAA antagonist. A feature of the single channel currents was their variable amplitude: they had a maximum conductance of ca. 70 pS and displayed many lower conductance states that were integral multiples of 5-6 pS. In several cells exposed to GABA or baclofen, first small currents and then progressively larger currents appeared: current amplitude was a multiple of an elementary current. It is suggested that binding of GABA to GABAB receptors activates a second messenger system causing opening of oligomeric potassium channels.

Animals↗
PubMed1991

Potassium channels and epilepsy: evidence that the epileptogenic toxin, dendrotoxin, binds to potassium channel proteins.

Dendrotoxin-I, a component of the venom of the black mamba snake, Dendroaspis polylepsis, was used to affinity purify a potassium channel from bovine brain. This dendrotoxin-I binding protein was composed of several subunits with molecular weights of 35,000, 38,000, 42,000 and 74,000. Partial sequence resulting from Edman degradation of the N-terminus of the 74 kDa subunit was identical to the predicted amino acid sequence of the N-terminus of a protein encoded by a mouse/rat homologue of the Shaker gene family of potassium channels, MK2/RBK2 (RCK5). Polyclonal antibodies raised against synthetic peptides derived from the predicted amino acid sequence of another member of this family, MK1, recognized this 74 kDa subunit. Due to extensive amino acid sequence identity between MK2 and MK1, it is likely that antibodies recognized epitopes common to both. Thus, from an immunological standpoint, either MK1, MK2, or both channel proteins could have been present in this 74 kDa band on protein blots. Closely related K+ channels in bovine brain could have copurified based on their affinity for dendrotoxin-I (DTX-I). DTX-I was shown to inhibit MK1 currents in a time and voltage independent fashion. Physiological and molecular evidence indicates the existence of many types of DTX sensitive potassium channels in the mammalian brain, however, our protein sequencing of the 74 kDa subunit has detected the presence of only one unique N-terminal sequence, identical to MK2. The possible reason for the appearance of this discrepancy is discussed. This paper represents the first report identifying one dendrotoxin binding protein in bovine brain tissue (BK2) as a delayed rectifier type of potassium channel.

Amino Acid Sequence↗
PubMed1990

Two different types of potassium channels in human skeletal muscle activated by potassium channel openers.

The inside-out patch clamp technique was used to record the effects of K+ channel openers (EMD 52692, RP 49356 and Cromakalim) on single channel currents in membrane blebs of human skeletal muscle. Two types of K+ channels were activated by these drugs: an ATP-sensitive K+ channel which was inhibited by 3 mM ATP and 5 microM Glibenclamide and an ATP insensitive K+ channel. The open probability of both types was strongly increased by K+ channel openers. Glibenclamide antagonized the action of the K+ channel openers.

Adenosine Triphosphate↗
PubMed1991

Inhibition of aldosterone production and angiotensin action by drugs affecting potassium channels.

We screened potassium channel agonists and antagonists in a search for pharmacologic probes of the channels that mediate potassium's effects on adrenal zona glomerulosa cells. Suspensions of bovine cells were tested, and aldosterone was measured by radioimmunoassay. The most potent inhibitors were pinacidil, capsaicin, glyburide, and quinine. These reagents were more potent against aldosterone production than against cortisol production. Aldosterone produced under basal conditions, as well as that stimulated by potassium, angiotensin II, or dibutyryl cyclic AMP, was antagonized. The vasodilatory and aldosterone-inhibiting potencies of potassium channel reagents were very different. Candidate antihypertensives with potassium channel activity should be tested for adrenal inhibition.

Adenosine Triphosphate↗
PubMed1990

How might the diversity of potassium channels be generated?

Potassium channels are a diverse group of ion channels present in most eukaryotic cells that have been examined. Over 30 different potassium channels have been characterized biophysically. They show different sensitivities to voltage and/or intracellular messengers, and have different kinetic or pharmacological properties. The wide range of potassium channel properties reflects the broad spectrum of cellular functions that they serve, including control of synaptic efficacy, of heart beat, and of endocrine and exocrine secretion. How might this tremendous diversity of potassium channels be generated? Partial answers have begun to emerge as molecular studies of potassium channel genes have become possible over the past few years.

Animals↗
PubMed1992

Substance P opens cation channels and closes potassium channels in rat locus coeruleus neurons.

Whole-cell recordings were made from neurons of the rat locus coeruleus in a tissue slice removed from rat brain. Substance P caused an inward current in cells voltage-clamped at -60 mV. The effect of substance P was concentration-dependent (30 nM-3 microM) and was mimicked by similar concentrations of substance K and neuromedin K. The inward current resulted predominantly from an increase in membrane cation conductance; in potassium-free solutions it reversed polarity at about 12 mV. Substance P also reduced the conductance of an inwardly rectifying potassium current; this action was studied with low external sodium concentration. It is concluded that substance P excites rat locus coeruleus neurons by activating an intracellular transduction pathway leading to both cation conductance increase and potassium conductance decrease.

Animals↗
PubMed1992

Molecular cloning, characterization, and genomic localization of a human potassium channel gene.

Potassium (K+) channels are critical for a variety of cell functions, including modulation of action potentials, determination of resting membrane potential, and development of memory and learning. In addition to their role in regulating myocyte excitability, cardiac K+ channels control heart rate and coronary vascular tone and are implicated in the development of arrhythmias. We report here the cloning and sequencing of a k+ channel gene, KCNA1, derived from a human cardiac cDNA library and the chromosomal localization of the corresponding genomic clone. Oligonucleotides based on a delayed rectifier K+ channel gene were used in PCR reactions with human genomic DNA to amplify the S4-S6 regions of several different K+ channel genes. These sequences were used to isolate clones from a human cardiac cDNA library. We sequenced one of these clones, HCK1. HCK1 contains putative S2-S6 domains and shares approximately 70% sequence homology with previously isolated Shaker homologues. HCK1 was used to screen human cosmid libraries and a genomic clone was isolated. By sequencing the genomic clones, a putative S1 domain and translation initiation sequences were identified. Genomic mapping using human-rodent somatic cell panels and in situ hybridization with human metaphase chromosomes have localized KCNA1 to the distal short arm of human chromosome 12. This work is an important step in the study of human cardiac K+ channel structure and function and will be of use in the study of human inherited disease.

Amino Acid Sequence↗
PubMed1990

Biophysical and molecular mechanisms of Shaker potassium channel inactivation.

The potassium channels encoded by the Drosophila Shaker gene activate and inactivate rapidly when the membrane potential becomes more positive. Site-directed mutagenesis and single-channel patch-clamp recording were used to explore the molecular transitions that underlie inactivation in Shaker potassium channels expressed in Xenopus oocytes. A region near the amino terminus with an important role in inactivation has now been identified. The results suggest a model where this region forms a cytoplasmic domain that interacts with the open channel to cause inactivation.

Amino Acid Sequence↗
PubMed1990

Adenosine triphosphate-sensitive potassium channels in anoxia.

Potassium channels that are activated by decreasing adenosine trisphosphate levels are blocked by sulfonylurea drugs such as glibenclamide but are opened by diazoxide and some endogenous peptides. Judging from the effects of such drugs, it seems that in the hippocampus, these channels are present not on cell bodies but rather on glutamate-releasing nerve terminals (especially those of mossy fibers in the CA3 region). Because activation of these presynaptic potassium channels reduces anoxic glutamate release, they may be a useful target for specific drug therapy that might prevent the excitoxic effects of excessive glutamate release during anoxia/ischemia.

Adenosine Triphosphate↗
PubMed1991

1990: annus mirabilis of potassium channels.

Voltage-gated potassium channels make up a large molecular family of integral membrane proteins that are fundamentally involved in the generation of bioelectric signals such as nerve impulses. These proteins span the cell membrane, forming potassium-selective pores that are rapidly switched open or closed by changes in membrane voltage. After the cloning of the first potassium channel over 3 years ago, recombinant DNA manipulation of potassium channel genes is now leading to a molecular understanding of potassium channel behavior. During the past year, functional domains responsible for channel gating and potassium selectivity have been identified, and detailed structural pictures underlying these functions are beginning to emerge.

Action Potentials↗
PubMed1992

Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel.

Voltage-gated potassium channels play important functional roles in the development and maintenance of human lymphocyte functions. One such channel, known as the type n channel, has been well defined in human T cells and exhibits unique functional properties that distinguish it from other species of potassium channels. We report the characterization of a human genomic DNA clone, HGK5, encoding a 523-amino-acid potassium channel protein encoded by an open reading frame on a single exon. RNA transcribed in vitro from HGK5 genomic DNA directs expression of functional voltage-dependent potassium currents in Xenopus oocytes. The functional characteristics of the expressed channels are strikingly similar to those of the type n channel on human T lymphocytes. This, together with the presence of significant levels of HGK5 mRNA in human T lymphocytes, supports the notion that HGK5 encodes the human type n voltage-gated potassium channel. The effects of concanavalin A treatment on HGK5 mRNA levels in cultured human T lymphocytes was also examined. Mitogenic concentrations of concanavalin A induced a time-dependent decrease in HGK5 mRNA levels, suggesting that previously observed increases in potassium current density following concanavalin A treatment of human T lymphocytes are not due to increased transcriptional activity of the type n potassium channel gene.

Amino Acid Sequence↗
PubMed1990

Reduction of ischemic damage in isolated rat hearts by the potassium channel opener, RP 52891.

Potassium channel activators have been shown to protect ischemic myocardium. We studied the ability of the novel potassium channel activator, RP 52891, to also reduce ischemic damage in isolated globally ischemic rat hearts. RP 52891 (1-100 microM) was given before the hearts were subjected to 25 min of ischemia and 30 min of reperfusion. Before ischemia, RP 52891 reduced contractile function only at the highest concentration (100 microM). Significant reductions in ischemic damage were observed at 3 microM and higher concentrations. RP 52891 improved reperfusion contractile function and reduced lactate dehydrogenase release. Contracture was significantly reduced by RP 52891 during reperfusion. The protective effects of RP 52891 were completely reversed by glyburide and sodium 5-hydroxydecanoate, both blockers of ATP-sensitive potassium channels. Thus, RP 52891 has direct cardioprotective efficacy, which may be related to activation of ATP-sensitive potassium channels.

Adenosine Triphosphate↗