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PubMed2003

Properties and functional role of voltage-dependent potassium channels in dendrites of rat cerebellar Purkinje neurons.

We characterized the properties and functional roles of voltage-dependent potassium channels in the dendrites of Purkinje neurons studied in rat cerebellar slices. Using outside-out patches formed <or=250 microm away from the soma, we found that depolarization-activated potassium channels were present at high density throughout the dendritic tree. Currents required relatively large depolarizations for activation (midpoint, approximately -10 mV), had rapid activation and deactivation kinetics, and inactivated partially (20-70% over 200 msec) with both fast (time constant, 15-20 msec) and slow (300-400 msec) components. Inactivating and noninactivating components were both blocked potently by external tetraethylammonium (half-block by 150 microm) and 4-aminopyridine (half-block by 110 microm). The voltage dependence, kinetics, and pharmacology suggest a predominant contribution by Kv3 family subunits, and immunocytochemical experiments showed staining for both Kv3.3 and Kv3.4 subunits in the dendritic tree. In the proximal dendrite, potassium channels were activated by passively spread sodium spikes recorded at the same position, and experiments using dual recordings showed that the channels serve to actively dampen back-propagation of somatic sodium spikes. In more distal dendrites, potassium currents were activated by voltage waveforms taken from climbing fiber responses, suggesting that they help shape these responses as well. The requirement for large depolarizations allows dendritic Kv3 channels to shape large depolarizing events while not disrupting spatial and temporal summation of smaller excitatory postsynaptic potentials.

Action Potentials↗
PubMed1999

Structure and function of cardiac potassium channels.

Recent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm-1P subunits generally function as inwardly rectifying K(+)-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1-S6). The S5-P-S6 section resembles the 2Tm-1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm-1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit-subunit interactions. The 6Tm-1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm-1P subunits (4Tm-2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm-1P subunits encodes the 'funny' pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm-1P channel enhances the outlook for more refined molecular approaches.

Action Potentials↗
PubMed2003

Natural modulators of large-conductance calcium-activated potassium channels.

Large-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cell, including neurons and myocytes, where they play an essential role in the regulation of cell excitability and function. These properties open a possible role for BK-activators (also called BK-openers) and/or BK-blockers as effective therapeutic agents for different neurological, urological, respiratory and cardiovascular diseases. The synthetic benzimidazolone derivatives NS004 and NS1619 are the pioneer BK-activators and have represented the reference models which led to the design of several novel and heterogeneous synthetic BK-openers, while very few synthetic BK-blockers have been reported. Even today, the research towards identifying new BK-modulating agents is proceeding with great impetus and is giving an ever-increasing number of new molecules. Among these, also a handsome number of natural BK-modulator compounds, belonging to different structural classes, has appeared in the literature. The goal of this paper is to provide a possible simple classification of the broad structural heterogeneity of the natural BK-activating agents (terpenes, phenols, flavonoids) and blockers (alkaloids and peptides), and a concise overview of their chemical and pharmacological properties as well as potential therapeutic applications.

Benzimidazoles↗
PubMed1997

Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4 segment.

1. Rat eag potassium channels (r-eag) were expressed in Xenopus oocytes. They gave rise to delayed rectifying K+ currents with a strong Cole-Moore effect. 2. Deletions in the N-terminal structure of r-eag either shifted the activation threshold to more negative potentials and slowed the activation kinetics (delta 2-190, delta 2-12 and delta 7-12) or resulted in a shift to more positive potentials and faster activation kinetics (delta 150-162). 3. The impact of the deletion delta 7-12 was investigated in more detail: it almost abolished the Cole-Moore effect and markedly slowed down channel deactivation. 4. Unlike wild-type channels, the deletion mutants delta 7-12 exhibited a rapid inactivation which, in combination with the slow deactivation, resulted in current characteristics which were similar to those of the related potassium channel HERG. 5. Both the slowing of deactivation and the inactivation induced by the deletion delta 7-12 were compensated by a single histidine-to-arginine change in the S4 segment, while this mutation (H343R) only had minor effects on the gating kinetics of the full-length r-eag channel. 6. These results demonstrate a functional role of the N-terminus in the voltage-dependent gating of potassium channels which is presumably mediated by an interaction of the N-terminal protein structure with the S4 motif during the gating process.

Amino Acid Sequence↗
PubMed1993

Molecular cloning, functional expression and localization of an inward rectifier potassium channel in the mouse brain.

We have cloned an inward-rectifier potassium channel from a mouse brain cDNA library, studied its distribution in the brain by in situ hybridization and determined the chromosomal localization of the gene. A mouse brain cDNA library was screened using a fragment of the mouse macrophage IRK1 cDNA as a probe. Two duplicate clones of approximately 5.5 kb were obtained. Xenopus ococytes injected with cRNA derived from the clone expressed a potassium channel with inwardly rectifying channel characteristics. The amino acid sequence of the clone was identical to that of IRK1 recently cloned from a mouse macrophage cell line. In situ hybridization study showed the mouse brain IRK1 to be generally distributed throughout the brain, but in particular subsets of neurons at high levels. The gene was placed in the distal region of mouse chromosome 11, which contains several uncloned neurological mutations. These results provide the first demonstration of the cloning and distribution of an inward rectifier potassium channel from the nervous system.

Animals↗
PubMed1996

Acidosis-induced coronary arteriolar dilation is mediated by ATP-sensitive potassium channels in vascular smooth muscle.

Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulations during hypoxia, ischemia, and increased metabolic demand of the heart, its vasomotor control mechanism has not been elucidated. To examine the effect of acidosis of vasomotor tone, porcine coronary arterioles (40 to 110 microns) were isolated, cannulated, and pressurized to 60 cm H2O intraluminal pressure without flow for in vitro study. Acidosis (pH 7.4 to 7.0) was produced by adding HCl to the extravascular solution. The involvement of potassium channels in the vasomotor response to acidosis was evaluated by using BaCl2 (100 mumol/L, nonspecific potassium channel inhibitor), glibenclamide (5 mumol/L, ATP-sensitive potassium channel inhibitor), and iberiotoxin (100 nmol/L, calcium-activated potassium channel inhibitor). To determine whether endothelial hyperpolarization contributes to the acidosis-induced dilation, the pH-diameter relation of the vessel was examined under a high intraluminal concentration of KCl (40 mmol/L). The involvement of nitric oxide and prostaglandins was assessed by using NG-monomethyl-L-arginine (L-NMMA, 10 mumol/L) and indomethacin (10 mumol/L), respectively. To evaluate the role of endothelium in the acidosis-induced dilation, the pH-diameter relation was studied after endothelial removal. All vessels developed a similar level of spontaneous tone (internal diameter, 75 +/- 4 microns [approximately 69 +/- 1% of maximum diameter) and dilated to HCl in dose-dependent manner. Glibenclamide completely abolished vasodilation to a mild level of acidosis (pH 7.2 to 7.3) and attenuated the vasodilation by 70% at pH 7.0. Acidosis-induced dilation was also inhibited by BaCl2 but not by iberiotoxin. L-NMMA, indomethacin, and intraluminal KCl did not alter the pH-diameter relation. Vasodilation to acidosis of the endothelium-denuded vessels was identical to that of the endothelium-intact vessels. In addition, glibenclamide attenuated the acidosis-induced arteriolar dilation of endothelium-denuded vessels. These results suggest that the opening of ATP-sensitive potassium channels in vascular smooth muscle mediates the coronary arteriolar dilation during acidosis.

Animals↗
PubMed2006

Chronic inhibition of cardiac Kir2.1 and HERG potassium channels by celastrol with dual effects on both ion conductivity and protein trafficking.

A high percentage of drugs and drug candidates has been found to cause cardiotoxicity by reducing potassium conductance, more commonly known as QT prolongation. However, some compounds do not show direct block of ionic flow, suggesting that other mechanisms may also lead to reduction of potassium currents. Using the functional recovery after chemobleaching (FRAC) assay, we have examined a collection of drugs and drug-like compounds for potential perturbation of cardiac potassium channel trafficking. Here we report that a significant number of inhibitory compounds displayed effects on channel expression on the cell surface. Further investigation of celastrol (3-hydroxy-24-nor-2-oxo-1 (10),3,5,7-friedelatetraen-29-oic acid), a cell-permeable dienonephenolic triterpene compound, revealed its potent inhibitory activity on both Kir2.1 and hERG potassium channels, causal to QT prolongation. In addition to acute block of ion conduction, celastrol also alters the rate of ion channel transport and causes a reduction of channel density on the cell surface. In contrast, celastrol has no effects on trafficking of either CD4 or CD8 membrane proteins. Furthermore, the potency for reducing surface expression is approximately 5-10-fold more effective than that for either direct acute inhibition or reported cytoprotectivity via activation of the heat shock transcription factor 1. Because the reduction of potassium channel activity is a common form of druginduced cardiotoxicity, the potent inhibition of cell surface expression by celastrol underscores a need to evaluate drug candidates for their chronic effects on biogenesis of potassium channels. Our results suggest that chronic exposure to certain drugs may be an important aspect of acquired QT prolongation.

Acetates↗
PubMed1996

Structural and functional characterization of human potassium channel subunit beta 1 (KCNA1B).

Voltage-activated Shaker-related potassium channels (kv1) consist of alpha and beta subunits. We have analysed the structure of the human KCNA1B (hKv beta 1) gene. KCNA1B is > 250 kb in size and encodes at least three Kv beta 1 splice variants. The Kv beta 1 open reading frame is divided into 14 exons. In contrast, genes coding for family members of KCNA (Kv 1 alpha) subunits are markedly smaller and have intronless open reading frames. The expression of Kv 1 alpha and Kv beta mRNA was compared in Northern blots of poly(A+) RNA isolated from various human brain tissues. The results suggest an intricate and cell-specific regulation of Kv 1 alpha and Kv beta mRNA synthesis such that distinct combinations of alpha and beta subunits would occur in different nuclei of the brain. The splice variants hKv beta 1.1 and hKv beta 1.2 were functionally characterized in coexpression studies with hKv 1.5 alpha subunits in 293 cells. It is shown that the confer rapid inactivation on hKv 1.5 channels with different potencies. This may be due to differences in their amino terminal sequences and/or inactivating domains. It is also shown that the amino terminal Kv beta 1.1 and Kv 1.4 alpha inactivating domains compete with each other, probably for the binding to the same receptor site(s) on Kv 1 alpha-subunits.

Amino Acid Sequence↗
PubMed1994

Potassium channels of pig articular chondrocytes are blocked by propofol.

The effect of propofol on the voltage-activated potassium channels in pig articular chondrocytes was investigated. Propofol was found to reversibly block the potassium channels in a dose-dependent manner. The blocking effect was voltage-independent and the Hill coefficient was 1.85 +/- 0.18. No changes either in the slope conductance or in the single channel kinetics were observed. The half-blocking concentration (Ec50) was 6.0 +/- 0.49 microM which is much lower than the concentrations used to observe the scavenging effect of the drug in an artificial synovial fluid. Interestingly, Ec50 found in our experiments is also smaller than the blood concentration of propofol used in anaesthesia. These results show that propofol may strongly affect the potassium channels in some non-excitable cells.

Animals↗
PubMed1996

Kv beta 1 subunit binding specific for shaker-related potassium channel alpha subunits.

Voltage-activated potassium (Kv) channels from mammalian brain are hetero-oligomers containing alpha and beta subunits. Coexpression of Kv1 alpha and Kv beta 1 subunits confers rapid A-type inactivation on noninactivating potassium channels (delayed rectifiers) in expression systems in vitro. We have delineated a Kv1.5 aminoterminal region of up to 90 amino acids (residues 112-201) that is sufficient for interactions of Kv1.5 alpha and Kv beta 1 subunits. Within this region of the Kv1.5 amino terminus (residues 193-201), a Kv beta 1 interaction site necessary for Kv beta 1-mediated rapid inactivation of Kv1.5 currents was detected. This interaction site motif (FYE/QLGE/DEAM/L) is found exclusively in the Shaker-related subfamily (Kv1). The results show that hetero-oligomerization between alpha and Kv beta 1 subunits is restricted to Shaker-related potassium channel alpha subunits.

Amino Acid Sequence↗
PubMed2002

Inhibitory effects of potassium channel blockers on tetramethylpyrazine-induced relaxation of rat aortic strip in vitro.

Tetramethylpyrazine (TMP) is one of the active principles contained in Ligusticum chuanxiong Hort. (Umbelliferae), a herb that has been widely used to treat vascular disorders in China. In the present study, role of potassium channel in the vasodilatation of TMP was investigated using the effect of potassium channel blocker on TMP induced relaxation in isolated aortic rings from Wistar rats. TMP produced a concentration-dependent relaxation in the aortic rings precontracted with vasopressin or phenylephrine. Similar effect of TMP on vasoconstrictions by phenylephrine and vasopressin, induced through two different receptors, indicating the direct vasodilatation of TMP. Specific inhibitors for potassium channel were used to characterize the role of potassium channel in this action of TMP. Only the inhibitors specific to small conductance calcium-activated potassium (SK(Ca)) channel or ATP-sensitive potassium (K(ATP)) channel inhibited the action of TMP. Also, the TMP-induced relaxation was reversed by the inhibitor of soluble guanylyl cyclase in a way similar to that of K(ATP) channel blockade. The obtained results indicated that vasodilatation induced by TMP is related to the opening of SK(Ca) and K(ATP) channels.

Animals↗
PubMed2003

Potassium channel gating observed with site-directed mass tagging.

Potassium channels allow the selective flow of K+ ions across otherwise impermeable membranes. During a process called gating, these channels undergo a conformational change that proceeds from a closed to an open state. The closed state of KcsA, a prokaryotic potassium channel, has been structurally well characterized with equilibrium structural techniques. However, attempts to obtain a structural description of the gating transition of the channel have been hampered because the open state is only transiently occupied and, therefore, not readily accessible to such techniques. Here we describe a non-equilibrium technique that we call site-directed mass tagging and use this technique to probe the conformational change that KcsA undergoes during gating. The results indicate that KcsA is a dynamically modular molecule; the extracellular half of the membrane-spanning region is held rigid during gating, while the intracellular half undergoes a significant conformational change.

Bacterial Proteins↗
PubMed1991

Functions and distribution of voltage-gated sodium and potassium channels in mammalian Schwann cells.

Recent patch-clamp studies on freshly isolated mammalian Schwann cells suggest that voltage-gated sodium and potassium channels, first demonstrated in cells under culture conditions, are present in vivo. The expression of these channels, at least at the cell body region, appears to be dependent on the myelinogenic and proliferative states of the Schwann cell. Specifically, myelin elaboration is accompanied by a down regulation of functional potassium channel density at the cell body. One possibility to account for this is a progressive regionalization of ion channels on a Schwann cell during myelin formation. In adult myelinating Schwann cells, voltage-gated potassium channels appear to be localized at the paranodal region. Theoretical calculations have been made of activity-dependent potassium accumulations in various compartments of a mature myelinated nerve fibre; the largest potassium accumulation occurs not at the nodal gap but rather at the adjacent 2-4 microns length of periaxonal space at the paranodal junction. Schwann cell potassium channels at the paranode may contribute to ionic regulation during nerve activities.

Animals↗
PubMed1992

[Function and pharmacology of potassium channels in heart and vessels].

The variability of the potassium channels in the cardiac tissues is remarkable. There are two main classes: voltage-operated channels and ligand-operated channels. The voltage-operated channels play a dominant role in the genesis of the resting potential (iK1) and the different phases of the action potential, the transient current ito during the initial phase of repolarisation, the iKp current and the slow current iK during the plateau phase. This class also includes the acetylcholine activated channel, iK(Ach). The ligand-operated channels seem to play a role in pathological situations such as ischaemia and anoxia: these channels are activated by a reduction in intracellular ATP or an increase in intracellular fatty acids or Na+. Substances blocking the iK and ito potassium channels have an anti-ischaemic effect. The agonists of ATP channels have a great therapeutic potential in vascular pathology, especially in the treatment of hypertension.

Action Potentials↗
PubMed1998

Thyroid hormone regulates expression of shaker-related potassium channel mRNA in rat heart.

Effects of thyroid hormones on cardiac function or rhythm have been known; however, the mechanism is still unclear. In the present study examined were effects of triiodethyronine (T3) on voltage-gated potassium channel gene expression in rat heart since the potassium channels were presumed to modulate cardiac functions. The mRNA expression of five voltage-gated potassium channel gene alpha subunits (Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2) in heart was examined by ribonuclease protection assay in rats which were treated with T3 or propylthyouracil (PTU). All these genes except Kv1.4 mRNA were apparently expressed in the normal rat heart ventricle. Kv1.2 mRNA expression in ventricle was markedly suppressed by T3-treatment and enhanced by PTU-treatment. Interestingly, upregulation of Kv1.4 mRNA expression and downregulation of Kv1.5 mRNA expression were concomitantly induced in the ventricle by the PTU-treatment. In addition, the downregulation of the ventricular Kv1.5 mRNA expression induced by PTU was restored by T3 replacement. No changes of Kv2.1 and Kv4.2 mRNA expression were observed in the ventricles by the T3- or PTU-treatment. In heart atrium the same findings were observed. Kv1.4 mRNA expression, which was detectable in control rat atrium, also decreased significantly by T3-treatment. In contrast, no changes of Kv1.2, Kv1.4, and Kv1.5 mRNA expression in rat brains were induced by T3-treatment. These findings suggest that thyroid hormone specifically influences mRNA expression of Shaker-related potassium channel genes in rat hearts through a common T3 receptor-mediated regulation at a transcriptional level.

Animals↗
PubMed2004

Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family.

It has recently been reported that dipeptidyl aminopeptidase X (DPPX) interacts with the voltage-gated potassium channel Kv4 and that co-expression of DPPX together with Kv4 pore forming alpha-subunits, and potassium channel interacting proteins (KChIPs), reconstitutes properties of native A-type potassium channels in vitro. Here we report the X-ray crystal structure of the extracellular domain of human DPPX determined at 3.0A resolution. This structure reveals the potential for a surface electrostatic change based on the protonation state of histidine. Subtle changes in extracellular pH might modulate the interaction of DPPX with Kv4.2 and possibly with other proteins. We propose models of DPPX interaction with the voltage-gated potassium channel complex. The dimeric structure of DPPX is highly homologous to the related protein DPP-IV. Comparison of the active sites of DPPX and DPP-IV reveals loss of the catalytic serine residue but the presence of an additional serine near the "active" site. However, the arrangement of residues is inconsistent with that of canonical serine proteases and DPPX is unlikely to function as a protease (dipeptidyl aminopeptidase).

Alternative Splicing↗
PubMed1995

Effect of selective inhibition of potassium channels on vasorelaxing response to cromakalim, nitroglycerin and nitric oxide of canine coronary arteries.

A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels. In isolated canine coronary arteries preconstricted with 25 microM prostaglandin F2 alpha, nitroglycerin (0.005-1.8 microM) and cromakalim (0.15-9.6 microM) produced dose-dependent vasodilations. Glibenclamide (30 microM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4-20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100-200 nM). Enhancement of potassium concentrations to 35.4-40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared. The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.

Animals↗
PubMed1987

Oscillatory activation of calcium-dependent potassium channels in HeLa cells induced by histamine H1 receptor stimulation: a single-channel study.

We have used the patch-clamp method (O.P. Hamill et al., Pfluegers Arch., 391:85-100, 1981) in order to investigate the activation pattern of a calcium-dependent potassium channel following H1 receptor stimulation in HeLa cells. Our results essentially indicate that the stimulation of H1 receptors by exogenous histamine at concentrations greater than 1 microM induces an oscillatory activation pattern of calcium-dependent potassium channels characterized by the occurrence of channel current bursts separated by long silent periods. It was also found that the occurrence of these bursts could be directly correlated with transmembrane potential oscillations, the latter being the resulting effect of the calcium-dependent potassium channel synchronous openings. In addition, the cyclic activation of the calcium-dependent potassium channels could be initiated by the addition of histamine to a calcium-free external medium, indicating that the stimulation of the H1 receptors in HeLa cells is mainly related to the release of calcium from internal stores. Finally, the membrane-permeable cyclic AMP analog dibutyryl cyclic AMP was found to be ineffective in initiating single-channel events such as those triggered by exogenous histamine. It is proposed that the oscillatory activation of the calcium-dependent potassium channels in HeLa cells results from a repetitive transient increase in cytosolic free calcium concentration consequent to the H1 receptor stimulation.

Adenylyl Cyclases↗