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PubMed1997

Inward rectifier potassium channels.

The past three years have seen remarkable progress in research on the molecular basis of inward rectification, with significant implications for basic understanding and pharmacological manipulation of cellular excitability. Expression cloning of the first inward rectifier K channel (Kir) genes provided the necessary break-through that has led to isolation of a family of related clones encoding channels with the essential functional properties of classical inward rectifiers, ATP-sensitive K channels, and muscarinic receptor-activated K channels. High-level expression of cloned channels led to the discovery that classical inward so-called anomalous rectification is caused by voltage-dependent block of the channel by polyamines and Mg2+ ions, and it is now clear that a similar mechanism results in inward rectification of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate receptor channels. Knowledge of the primary structures of Kir channels and the ability to mutate them also has led to the determination of many of the structural requirements of inward rectification.

Animals↗

PubMed2006

Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion.

Activation of the luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor (LHR) in cultured hypothalamic cells and immortalized GnRH (gonadotropin-releasing hormone) neurons (GT1-7 cells) transiently stimulates and subsequently inhibits cAMP production and pulsatile GnRH release. The marked and delayed impairment of cAMP signaling and episodic GnRH release in GT1-7 cells is prevented by pertussis toxin (PTX). This, and the LH-induced release of membrane-bound Galpha(s) and Galpha(i3) subunits, are indicative of differential G protein coupling to the LHR. Action potential (AP) firing in identified GnRH neurons also initially increased and then progressively decreased during LH treatment. The inhibitory action of LH on AP firing was also prevented by PTX. Reverse transcriptase-PCR analysis of GT1-7 neurons revealed the expression of G protein-gated inwardly rectifying potassium (GIRK) channels in these cells. The LH-induced currents were inhibited by PTX and were identified as GIRK currents. These responses indicate that agonist stimulation of endogenous LHR expressed in GnRH neurons activates GIRK channels, leading to suppression of membrane excitability and inhibition of AP firing. These findings demonstrate that regulation of GIRK channel function is a dominant factor in gonadotropin-induced abolition of pulsatile GnRH release. Furthermore, this mechanism could contribute to the suppression of pituitary function during pregnancy.

Action Potentials↗

PubMed1996

Effect of N-feruloyl tyramine (an analogue of tyramine) on inwardly rectifying potassium channel in frog ventricular myocytes.

Electrophysiological effects of N-feruloyl tyramine (NFT), an analogue of tyramine, on potassium currents in frog ventricular myocytes were examined using single-channel recording and whole-cell voltage clamp technique. Extracellular application of NFT induced a concentration-dependent decrease of macroscopic inward rectifier potassium current (iK1) with ID50 of 198 microM, while tyramine (100 microM) was ineffective in producing an inhibitory effect on iK1. NFT reduced the mean open time of iK1 to 1.3 ms from 3.1 ms in control without affecting the amplitude of single-channel conductance. It is indicated that boi containing NFT produces a prolongation of the plateau phase caused by the suppression of inwardly rectifying K channel. Thus, this prolongation may induce an increase in the inflow of Ca ions, which in turn leads to a positive inotropic effect.

Animals↗

PubMed1997

Modulation of inwardly rectifying potassium channels in cultured bovine pulmonary artery endothelial cells.

1. We have used the patch-clamp technique to study modulation of the inwardly rectifying K+ current (IK(IR)) in cultured bovine pulmonary artery endothelial cells (CPAE cells). In whole-cell mode, IK(IR) was defined as the Ba(2+)-sensitive current. In single channel recordings, we observed a strongly inwardly rectifying and K(+)-selective channel with a conductance of 31 +/- 3 pS. 2. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and functional data suggest that the endothelial IRK is most probably Kir2.1. 3. Intracellular ATP is required to prevent run-down of IRK in whole-cell mode. Single channel activity disappeared in inside-out patches exposed to ATP-free solution and in cell-attached patches on cells exposed to metabolic inhibition (KCN, 2-deoxyglucose). 4. The non-hydrolysable ATP analogues, ATP gamma S and adenylyl imidodiphosphate (AMP-PNP), did not prevent run-down. Run-down did not occur in the presence of okadaic acid, a phosphatase inhibitor, but was enhanced in the presence of protamine, an activator of phosphatase 2A (PP2A). 5. GTP gamma S and AlF4- inhibited IRK, also in the presence of ATP. GTP beta S antagonized the GTP gamma S effect. Pretreatment of the cells with PTX did not affect the GTP gamma S-induced inhibition. Okadaic acid, however, slowed this inhibition. 6. Neither activation of protein kinase A (PKA) nor activation of protein kinase C (PKC) affected IRK. Additionally, neither cytochalasin B nor a high concentration of intracellular Ca2+ affected the time course of IRK run-down. 7. We conclude that run-down of IRK is probably due to dephosphorylation by PP2A. Activation of a PTX-insensitive G protein inhibits this current by a mechanism that is neither mediated via the PKA and PKC pathways nor by intracellular Ca2+, but supposedly by a G protein-dependent activation of a phosphatase.

Adenosine Triphosphate↗

PubMed1993

An inwardly rectifying potassium channel in the basolateral membrane of sheep parotid secretory cells.

Using whole-cell patch-clamp techniques, we demonstrate that sheep parotid secretory cells have both inwardly and outwardly rectifying currents. The outwardly rectifying current, which is blocked by 10 mmol/liter tetraethylammonium (TEA) applied extracellularly, is probably carried by the 250 pS Ca(2+)- and voltage-activated K+ (BK) channel which has been described in previous studies. In contrast, the inwardly rectifying current, which is also carried by K+ ions, is not sensitive to TEA. It is similar to the inwardly rectifying currents observed in many excitable tissues in that (i) its conductance is dependent on the square root of the extracellular K+, (ii) the voltage range over which it is activated is influenced by the extracellular K+ concentration and (iii) it is blocked by the addition of Cs+ ions (670 mumol/liter) to the bathing solution. Our previously published cell-attached patch studies have shown that the channel type most commonly observed in the basolateral membrane of unstimulated sheep parotid secretory cells is a K+ channel with a conductance of 30 pS and, in this study, we find that its conductance also depends on the square root of the extracellular K+ concentration. It thus seems likely that it carries the inwardly rectifying K+ current seen in the whole-cell studies.

Animals↗

PubMed1996

A weakly inward rectifying potassium channel of the salmon brain. Glutamate 179 in the second transmembrane domain is insufficient for strong rectification.

A cDNA encoding for a weakly inward rectifying K+ channel (sWIRK: salmon weakly inward rectifying K+ channel) was isolated from the masu salmon brain by expression cloning. The sWIRK channel exhibited the highest similarity with members of the ROMK1 subfamily, BIR10/KAB-2 (70% amino acid identity) and ROMK1 (46%). An ATP binding motif which is characteristic of this subfamily was also conserved. The sWIRK RNA was detected in the brain, but not in the heart, kidney, skeletal muscle, liver, testis, and ovary. In the brain, the expression was observed in the ependymoglial cells on the surface of the ventricles as well as in the small perineuronal glia-like cells in the midbrain and the medulla. When compared with the strong inward rectifier IRK1 channel, the sWIRK channel showed a much weaker inward rectification property, and the activation kinetics upon hyperpolarization was slower and less voltage-dependent. The slope conductance of the single channel inward current was 37 pS (140 mM K+o), and outward current channel events were also observed. The weak rectification of sWIRK is significant in that it has a negatively charged residue (glutamate) in the M2 region which is reported to cause strong inward rectification. By introducing a point mutation to remove this negative charge (glutamine), the sWIRK E179Q mutant channel lost its inward rectification property completely, and the single channel property (45 pS; 140 mM K+o) was ohmic up to highly depolarized potential, even in the presence of the physiological cytoplasmic blockers such as Mg2+ and polyamines.

Amino Acid Sequence↗

PubMed1994

G protein-activated inwardly rectifying potassium channel (GIRK1/KGA) mRNA in adult rat heart and brain by in situ hybridization histochemistry.

GIRK1/KGA (referred to as GIRK1) is a member of the inwardly rectifying K+ channel family and is activated by G protein-linked receptors. The activation of this channel leads to hyperpolarization of the plasma membrane and is fundamental to the control of atrial and neuronal excitability. RNA blotting studies have shown that GIRK1 is expressed in the atrium of the heart and in the brain. We have used in situ hybridization histochemistry to characterize the pattern of expression of GIRK1 mRNA in adult rat heart and brain. In heart, expression of GIRK1 mRNA is homogeneous throughout the atria. There is no significant ventricular expression, although the conduction bundles were not specifically identified. GIRK1 mRNA expression in the brain is widespread with highest levels in the cortex, septum, hippocampus, thalamus, amygdala, cerebellum, and many nuclei of the midbrain and hindbrain, including red nucleus, inferior colliculus, pontine nucleus, nucleus of the solitary tract, and multiple cranial nerve nuclei (motor and sensory components). This detailed map of GIRK1 mRNA expression provides a basis for further study of this important new family of K+ channels.

Animals↗

PubMed1996

Cloning of a G protein-activated inwardly rectifying potassium channel from human cerebellum.

Based on sequence homology with the rat atrial G protein-coupled muscarinic potassium channel (GIRK1 or KGA1/KGB1), a human cDNA encoding a G protein-activated inwardly rectifying K+ channel (HGIRK1) was isolated. The cDNA encodes a protein of 501 amino acids and shares 99% identity to rat GIRK1 in its total amino acid sequence. Southern blot analysis of genomic DNA indicates a high degree of conservation among various species. In the human population a useful NlaIII restriction fragment length polymorphism was found in the coding sequence of HGIRK1. Co-expression of HGIRK1 and the 5-HT1A receptor in Xenopus oocytes resulted in opening of the channel upon treatment with serotonin. HGIRK1 currents showed strong inward rectification and could be blocked by extracellular Ba2+. Northern blot analysis shows that HGIRK1 expression in human is most abundant in the brain, while lower levels are round in kidney and heart.

Amino Acid Sequence↗

PubMed1995

Identification of domains conferring G protein regulation on inward rectifier potassium channels.

Cardiac m2 muscarinic acetylcholine receptors reduce heart rate by coupling to heterotrimeric (alpha beta gamma) guanine nucleotide-binding (G) proteins that activate IKACh, an inward rectifier K+ channel (IRK). Activation of the GIRK subunit of IKACh requires G beta gamma subunits; however, the structural basis of channel regulation is unknown. To determine which sequences confer G beta gamma regulation upon IRKs, we generated chimeric proteins composed of GIRK and RB-IRK2, a related, G protein-insensitive channel. Importantly, a chimeric channel containing the hydrophobic pore region of RB-IRK2 joined to the amino and carboxyl termini of GIRK exhibited voltage- and receptor-dependent activation in Xenopus oocytes. Furthermore, carboxy-terminal sequences specific to this chimera and GIRK bound G beta gamma subunits in vitro. Thus, G beta gamma may regulate IRKs by interacting with sequences adjacent to the putative channel pore.

Amino Acid Sequence↗

PubMed1995

Protein kinase C-mediated inhibition of an inward rectifier potassium channel by substance P in nucleus basalis neurons.

In nucleus basalis neurons, substance P (SP) causes a slow excitation, mediated through a pertussis toxin-insensitive G protein, by suppressing an inward rectifier K+ channel. Here we report that SP applied outside the patch pipette inhibited the single-channel activity, recorded on-cell, of the inward rectifier. The PKC inhibitors staurosporine and PKC(19-36) suppressed this effect in whole-cell mode and in on-cell single-channel mode. A diacylglycerol analog mimicked the SP effect, and PKC(19-36) suppressed this analog effect. SP irreversibly suppressed the inward rectifier in neurons treated with okadaic acid. These results indicate that a diffusible messenger mediates the SP effect, that its signal transduction involves phosphorylation by PKC, and that dephosphorylation by a serine/threonine protein phosphatase mediates its recovery.

Alkaloids↗

PubMed1992

cAMP-mediated expression of inwardly rectifying potassium channels in cultured mouse Schwann cells.

Voltage-gated ionic currents were recorded from freshly dissociated or cultured mouse Schwann cells obtained from neonatal sciatic nerves by the whole-cell variation of the patch-clamp technique. Schwann cells virtually lost inwardly rectifying potassium (Kir) currents within 2 days after nerve transection or in culture conditions of neonatal sciatic nerves confirming the previous results that axonal signals were suggested to play an important role in the expression of functional Kir channels. To see the effects of adenosine 3',5'-monophosphate (cAMP) analogues or forskolin on the expression of Kir channels in cultured Schwann cells, these agents were added to the culture medium 4 days after the start of the culture, when Kir currents were almost eliminated from cultured Schwann cells. Cultured Schwann cells restored the expression of Kir currents by co-culture with agents which elevate intracellular cAMP level. The dose-response of 8-(4-chlorophenylthio) (CPT) cAMP for the incidence of the expression of Kir currents showed a steep increase in the percentage of cells with Kir currents between 0.02 and 0.1 mM of external CPT cAMP and approximately two thirds of cells had Kir currents in higher concentrations of more than 0.1 mM of CPT cAMP after 4 days of incubation. After removal of CPT cAMP from the culture media after 4 days of incubation, Kir currents disappeared from cells within 2 days. The simultaneous application of cycloheximide (1 microgram/ml), an inhibitor of protein synthesis, with CPT cAMP suppressed the expression of Kir currents for up to 6 days of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart.

Single ventricular cells were enzymatically isolated from adult guinea-pig hearts (Isenberg & Klöckner, 1982). The patch-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981) was used to examine the conductance properties of an inward-rectifying K+ channel present in their sarcolemmal membrane. When the K+ concentration on the extracellular side of the patch was between 10.8 and 300 mM, inward current steps were observed at potentials more negative than the K+ equilibrium potential (EK). At more positive potentials no current steps were detectable, demonstrating the strong rectification of the channel. The zero-current potential extrapolated from the voltage dependence of the inward currents depends on the external K4 concentration [K+]o in a fashion expected for a predominantly K+-selective ion channel. It is shifted by 49 mV for a tenfold change in [K+]o. The conductance of the channel depends on the square root of [K+]o. In approximately symmetrical transmembrane K+ concentrations (145 mM-external K+), the single-channel conductance is 27 pS (at 19-23 degrees C). In normal Tyrode solution (5.4 mM-external K+) we calculate a single-channel conductance of 3.6 pS. The size of inward current steps at a fixed negative membrane potential V increases with [K+]o. The relation between step size and [K+]o shows saturation. Assuming a Michaelis-Menten scheme for binding of permeating K+ to the channel, an apparent binding constant of 210 mM is calculated for a membrane potential of -100 mV. For this potential the current at saturating [K+]o is estimated as 6.5 pA. The rectification of the single-channel conductance at membrane potentials positive to EK occurs within 1.5 ms of stepping the membrane potential from a potential of high conductance to one of low conductance. In addition to the main conductance state, the channel can adopt several substates of conductance. The main state could be the result of the simultaneous opening of four conducting subunits, each of which has a conductance of about 7 pS in 145 mM-external K+. The density of the inward-rectifying K+ channels in the ventricular sarcolemma is 0-10 channel/10 micron2 of surface membrane; the average of twenty-eight patches was 1 channel/1.8 micron2. It is concluded that the inward-rectifying K+ channels mediate the resting K+ conductance of ventricular heart muscle and the current termed IK1 in conventional voltage-clamp experiments.

Action Potentials↗

PubMed1995

Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes.

Xenopus oocytes expressed kappa-opioid specific binding sites after injection of cRNA prepared from a clone of the rat kappa-opioid receptor. Coinjection of kappa receptor cRNA with cRNA coding for a G protein-linked, inwardly rectifying, K+ channel (GIRK1, or KGA) resulted in oocytes that responded to the kappa agonist U-69593 by activating a large (1.0-1.5-microA) K+ current. U-69593 exhibited an EC50 of 260 +/- 50 nM and was blocked by the opioid antagonists norbinaltorphimine and naloxone. The kappa agonist bremazocine was 200-fold more potent than U-69593 in eliciting K+ current but exhibited a partial agonist profile in this expression system. The present results indicate that stimulation of inwardly rectifying K+ channels may be a potential effector mechanism for kappa-opioid receptors.

Amino Acid Sequence↗

PubMed1993

Inward-rectifying potassium channels in retinal glial (Müller) cells.

The voltage- and K(+)-dependent properties of Müller cell currents and channels were characterized in freshly dissociated salamander Müller cells. In whole-cell voltage-clamp experiments, cells with endfeet intact and cells missing endfeet both displayed strong inward rectification. The rectification was similar in shape in both groups of cells but currents were 9.2 times larger in cells with endfeet. Ba2+ at 100 microM reduced the inward current to 6.8% of control amplitude. Decreasing external K+ concentration shifted the cell current-voltage (I-V) relation in a hyperpolarizing direction and reduced current magnitude. In multichannel, cell-attached patch-clamp experiments, patches from both endfoot and soma membrane displayed strong inward rectification. Currents were 38 times larger in endfoot patches. In single-channel, cell-attached patch-clamp experiments, inward-rectifying K+ channels were, in almost all cases, the only channels present in patches of endfoot, proximal process, and soma membrane. Channel conductance was 27.8 pS in 98 mM external K+. Reducing external K+ shifted the channel reversal potential in a hyperpolarizing direction and reduced channel conductance. Channel open probability varied as a function of voltage, being reduced at more negative potentials. Together, these observations demonstrate that the principal ion channel in all Müller cell regions is an inward-rectifying K+ channel. Channel density is far higher on the cell endfoot than in other cell regions. Whole-cell I-V plots of cells bathed in 12, 7, 4, and 2.5 mM K+ were fit by an equation including Boltzmann relation terms representing channel rectification and channel open probability. This equation was incorporated into a model of K+ dynamics in the retina to evaluate the significance of inward-rectifying channels to the spatial buffering/K+ siphoning mechanism of K+ regulation. Compared with ohmic channels, inward-rectifying channels increased the rate of K+ clearance from the retina by 23% for a 1 mM K+ increase and by 137% for a 9.5 mM K+ increase, demonstrating that Müller cell inward-rectifying channels enhance K+ regulation in the retina.

Ambystoma↗

PubMed2001

Activation of barium-sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles.

BACKGROUND: Conducted vasodilation seems to be critical for the functional distribution of blood flow in the skeletal muscle microcirculation. However, this vasoregulatory phenomenon has not been documented in the coronary microcirculation, and its underlying mechanism remains elusive. Because potassium ions are potent metabolic vasodilators in the heart, by activating vascular inward rectifier K(+) (K(ir)) channels, we tested the hypothesis that coronary arterioles exhibit remote vasodilation through activation of this type of channel. METHODS AND RESULTS: Porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. Vessels dilated concentration-dependently to extraluminal KCl (5 to 20 mmol/L), bradykinin, adenosine, pinacidil, and sodium nitroprusside. A K(ir) channel blocker, BaCl(2) (30 micromol/L), inhibited vasodilatory responses to KCl and bradykinin but not to adenosine, pinacidil, or nitroprusside. In a flow chamber, localized administration of bradykinin, adenosine, and KCl to the downstream end of the arterioles caused approximately 80% dilation at the site of drug application (local site) and also produced 30% to 60% dilation at the upstream end of arterioles (remote site). Nitroprusside produced a similar dilation at the local site but failed to initiate remote vasodilation. In the presence of Ba(2+), adenosine still dilated the local site, but the local dilations to bradykinin and KCl and the remote dilations to adenosine, bradykinin, and KCl were inhibited. CONCLUSIONS: We demonstrated that some modes of local vasodilation can be conducted to remote sites in coronary arterioles and that local and remote dilations can occur through different vasodilatory mechanisms. Activation of K(ir) channels seems critical for some agonist-induced local vasodilations and also for the initiation and/or transmission of signals causing remote vasodilation.

Adenosine↗

PubMed1998

Expression of TWIK-1, a novel weakly inward rectifying potassium channel in rat kidney.

Several K+ conductances have been identified in the kidney, with specific properties and localization in distinct cell types and membrane domains. On the other hand, several K+ channels have been characterized at the molecular level. By immunolocalization, we show that a new inward rectifying K+ channel, TWIK-1, is specifically expressed in distinct tubular segments and cell types of the rat kidney. In the proximal tubule, TWIK-1 prevails in the initial portions (convoluted part), where it is restricted to the apical (brush-border) membrane. In the collecting duct, immunofluorescence was intracellular or confined to the apical membrane and restricted to intercalated cells, i.e., in cells lacking aquaporin-2, as shown by double immunofluorescence. TWIK was also expressed in medullary and cortical parts of the thick limb of the loop of Henle, identified with an anti-Tamm-Horsfall protein antibody (double immunofluorescence). The intensity of TWIK-1 immunolabeling was unchanged in rats fed a low-Na+ or a low-K+ diet. Because TWIK-1 shares common properties with the low-conductance apical K+ channel of the collecting duct, we propose that it could play a role in K+ secretion, complementary to ROMK, another recently characterized K+ channel located in principal cells of the cortical collecting duct and in the loop of Henle.

Animals↗

PubMed1989

Inward rectifying potassium channels in human malignant glioma cells.

Human glioma cells obtained from established cell lines (Tp-276MG, Tp-301MG, Tp-378MG, Tp-483MG and U-251MG) were analyzed for the presence of ion channels with the tight-seal voltage clamp technique. The current-voltage relation revealed a marked inward rectification at hyperpolarizing voltages, due to the presence of inward rectifying K-channels in cells from all studied cell lines. These channels were conducting when the membrane potential was more negative than the K-equilibrium potential. The slope conductance for the inward K-currents (gKi) was affected both by [K+]i and [K+]o. gKi was proportional to [K+]o raised to 0.35 or 0.50, of which the larger value was measured in the presence of low [K+]i (25 mM). The rectification was not significantly different in cells perfused with Mg-free EDTA-buffered internal solution. Tl+ was 3.5 times more permanent than K+. gKi was blocked by Cs+ (1 mM) in a voltage-dependent way (more effective in the hyperpolarized membrane), and by Na+ (154 mM) depending on voltage and time. From measurements of unitary current events in membrane patches (outside out or cell attached) the conductance of the single inward rectifying channel was estimated to be 27 +/- 7 pS. This type of ion channel may be important for K-uptake by glial cells and hence for the K-homeostasis in the brain.

4-Aminopyridine↗

PubMed1979

A voltage-dependent gate in series with the inwardly rectifying potassium channel in frog striated muscle.

1. The degree of tubular potassium depletion and the decrease of potassium conductance due to hyperpolarizing pulses in striated muscular fibres have been examined with the three micro-electrode voltage-clamp technique. 2. The conductance of the fibre membrane has been measured in different extracellular K+ concentrations from 1 to 10 mM. 3. Comparison of the two sets of measurements shows that changes in tubular K+ concentration are not sufficient to account for the conductance decrease associated with hyperpolarization. 4. The presence of a voltage-dependent gate in series with the inwardly rectifying channel for K+ ions, suggested by Almers (1972a, b), is thus confirmed.

Animals↗