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Results for “Delayed Rectifier Potassium Channels”

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PubMed2003

Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model.

To elucidate the dynamical mechanisms of the sinoatrial (SA) node pacemaker activity, we investigated the roles of L-type Ca2+ (ICa,L) and delayed-rectifier K+ (IKr) currents in pacemaking by stability and bifurcation analyses of our rabbit SA node model (Kurata Y, Hisatome I, Imanishi S, and Shibamoto T. Am J Physiol Heart Circ Physiol 283: H2074-H2101, 2002). Equilibrium points (EPs), periodic orbits, stability of EPs, and Hopf bifurcation points were calculated as functions of conductance or gating time constants of the currents for constructing bifurcation diagrams. Structural stability (robustness) of the system was also evaluated by computing stability and dynamics during applications of constant bias currents (Ibias). Blocking ICa,L or IKr caused stabilization of an EP and cessation of pacemaking via a Hopf bifurcation. The unstable zero-current potential region determined with Ibias applications, where spontaneous oscillations appear, shrunk and finally disappeared as ICa,L diminished, but shrunk little when IKr was eliminated. The reduced system, including no time-dependent current except ICa,L, exhibited pacemaker activity. These results suggest that ICa,L is responsible for EP instability and pacemaker generation, whereas IKr is not necessarily required for constructing a pacemaker cell system. We further explored the effects of various K+ currents with different kinetics on stability and dynamics of the model cell. The original IKr of delayed activation and inward rectification appeared to be most favorable for generating large-amplitude oscillations with stable frequency, suggesting that IKr acts as an oscillation amplifier and frequency stabilizer. IKr may also play an important role in preventing bifurcation to quiescence of the system.

Animals↗

PubMed2001

Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms.

Zinc and copper are highly concentrated in several mammalian brain regions, including the olfactory bulb and hippocampus. Whole cell electrophysiological recordings were made from rat olfactory bulb neurons in primary culture to compare the effects of zinc and copper on synaptic transmission and voltage-gated ion channels. Application of either zinc or copper eliminated GABA-mediated spontaneous inhibitory postsynaptic potentials. However, in contrast to the similarity of their effects on inhibitory transmission, spontaneous glutamate-mediated excitatory synaptic activity was completely blocked by copper but only inhibited by zinc. Among voltage-gated ion channels, zinc or copper inhibited TTX-sensitive sodium channels and delayed rectifier-type potassium channels but did not prevent the firing of evoked single action potentials or dramatically alter their kinetics. Zinc and copper had distinct effects on transient A-type potassium currents. Whereas copper only inhibited the A-type current, zinc modulation of A-type currents resulted in either potentiation or inhibition of the current depending on the membrane potential. The effects of zinc and copper on potassium channels likely underlie their effects on repetitive firing in response to long-duration step depolarizations. Copper reduced repetitive firing independent of the initial membrane voltage. In contrast, whereas zinc reduced repetitive firing at membrane potentials associated with zinc-mediated enhancement of the A-type current (-50 mV), in a significant proportion of neurons, zinc increased repetitive firing at membrane potentials associated with zinc-mediated inhibition of the A-type current (-90 mV). Application of zinc or copper also inhibited voltage-gated Ca(2+) channels, suggesting a possible role for presynaptic modulation of neurotransmitter release. Despite similarities between the effects of zinc and copper on some ligand- and voltage-gated ion channels, these data suggest that their net effects likely contribute to differential modulation of neuronal excitability.

Action Potentials↗

PubMed2002

Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block.

BACKGROUND: The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood. METHODS AND RESULTS: We created a rabbit model with chronic complete atrioventricular block (AVB) (n=34), which showed prominent QT prolongation (by 120%), high incidence of spontaneous TdP (71%), and cardiac hypertrophy. Patch-clamp experiments were performed in left ventricular myocytes from 9 rabbits (8 with TdP, 1 without TdP) at approximately 21 days of AVB and from 8 sham-operated controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (+61% at 0.5 Hz, +21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K(+) current (I(Kr) and I(Ks)) in AVB myocytes were significantly smaller than in control by 50% and 55%, respectively. There was no significant difference in Ca(2+)-independent transient outward current (I(to1)). L-type Ca(2+) current (I(Ca,L)) in control and AVB myocytes was similar in peak amplitude, but the half voltage for activation was shifted to the negative direction (5.9 mV) in AVB myocytes. Voltage dependence of I(Ca,L) inactivation was not different in control and AVB myocytes. The inward rectifier K(+) current (I(K1)) significantly increased in AVB myocytes compared with control. CONCLUSIONS: In the rabbit, chronic AVB leads to prominent QT prolongation and high incidence of spontaneous TdP. Downregulation of both I(Kr) and I(Ks) in association with altered I(Ca,L) activation kinetics may underlie the arrhythmogenic ventricular remodeling.

Action Potentials↗

PubMed2004

Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) downregulates atrial transient outward (I(to)), slow delayed rectifier (I(Ks)), and L-type Ca(2+) (I(Ca,L)) currents and upregulates Na(+)-Ca(2+) exchange current (I(NCX)) (ionic remodeling) and causes atrial fibrosis (structural remodeling). The relative importance of ionic versus structural remodeling in CHF-related atrial fibrillation (AF) is controversial. METHODS AND RESULTS: We measured hemodynamic and echocardiographic parameters, mean duration of burst pacing-induced AF (DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4 weeks (REC), and unpaced controls. Left ventricular ejection fraction averaged 58.6+/-1.2% (control), 36.2+/-2.3% (CHF, P<0.01), and 57.9+/-1.6% (REC), indicating full hemodynamic recovery. Similarly, left atrial pressures were 2.2+/-0.3 (control), 13.1+/-1.5 (CHF), and 2.4+/-0.4 (REC) mm Hg. CHF reduced I(to) density by approximately 65% (P<0.01), decreased I(Ca,L) density by approximately 50% (P<0.01), and diminished I(Ks) density by approximately 40% (P<0.01) while increasing I(NCX) density by approximately 110% (P<0.05). In REC, all ionic current densities returned to control values. DAF increased in CHF (1132+/-207 versus 14.3+/-8.8 seconds, control) and remained increased with REC (1014+/-252 seconds). Atrial fibrous tissue content also increased in CHF (2.1+/-0.2% for control versus 10.2+/-0.7% for CHF, P<0.01), with no recovery observed in REC (9.4+/-0.8%, P<0.01 versus control, P=NS versus CHF). CONCLUSIONS: With reversal of CHF, there is complete recovery of ionic remodeling, but the prolonged-AF substrate and structural remodeling remain. This suggests that structural, not ionic, remodeling is the primary contributor to AF maintenance in experimental CHF.

Animals↗

PubMed2006

Voltage-gated ion channels in dendrites of hippocampal pyramidal neurons.

The properties and distribution of voltage-gated ion channels contribute to electrical signaling in neuronal dendrites. The apical dendrites of CA1 pyramidal neurons in hippocampus express a wide variety of sodium, calcium, potassium, and other voltage-gated channels. In this report, we provide some new evidence for the role of the delayed-rectifier K(+) channel in shaping the dendritic action potential at different membrane potentials.

Action Potentials↗

PubMed1998

Voltage-gated potassium channels of Schwann cells from trout lateral line nerve: a combined electrophysiological and molecular characterization.

Voltage-gated ionic currents were recorded from explant cultured and freshly dissociated SC from trout lateral line nerve using the whole-cell configuration of the patch clamp technique. In the majority of cases a delayed rectifier potassium outward current (KD) was found exclusively, which activated at potentials > or = -40 mV and reached maximal amplitudes of 240+/-25.2 nA at 60 mV testpulse potential. This current showed no voltage-dependent kinetics of inactivation and was insensitive to TEA but was effectively blocked by 4-AP. By single cell RT-PCR the transcript of a shaker-related potassium channel gene, termed tshal (a fish homologue of Kv1.2), was selectively amplified. In its biophysical and pharmacological properties the native whole cell potassium outward current of trout Schwann cells closely matched those of the cloned tshal subunit previously expressed in xenopus oocytes. A small subpopulation of freshly dissociated SC (less than 10%) at hyperpolarizing potentials elicited a potassium inward current instead, which in its kinetics closely resembled the inward rectifier (KIR) of mammalian SC. Neither voltage-gated sodium currents nor membrane currents activated by excitatory amino acids (glutamate, kainate, and quisqualate) were observed.

Animals↗

PubMed2003

Effect of arvanil (N-arachidonoyl-vanillyl-amine), a nonpungent anandamide-capsaicin hybrid, on ion currents in NG108-15 neuronal cells.

The effects of arvanil (N-arachidonoyl-vanillyl-amine), a structural hybrid between capsaicin and anandamide, on ion currents in a mouse neuroblastoma and rat glioma hybrid cell line, NG108-15, were examined with the aid of the whole-cell voltage-clamp technique. Arvanil (0.2-50 microM) caused an inhibition of voltage-dependent L-type Ca(2+) current (I(Ca,L)) in a concentration-dependent manner. Arvanil produced no change in the overall shape of the current-voltage relationship of I(Ca,L). The IC(50) value of arvanil-induced inhibition of I(Ca,L) was 2 microM. Arvanil (5 microM) could shift the steady-state inactivation curve of I(Ca,L) to a more negative potential by approximately -15mV. No effect of arvanil (20 microM) on delayed rectifier K(+) current (I(K(DR))) was observed; however, capsaicin (20 microM), glyceryl nonivamide (20 microM) and capsinolol (20 microM) suppressed it significantly. Arvanil (20 microM) caused a slight reduction in the amplitude of erg (ether-à-go-go-related)-mediated K(+) current (I(K(erg))) without modifying the activation curve of this current, while capsaicin and glyceryl nonivamide were more effective in suppressing I(K(erg)). Under current-clamp configuration, arvanil decreased the firing frequency of action potentials. Arvanil-mediated inhibition of I(Ca,L) appeared to be independent of its binding to either vanilloid or cannabinoid receptors. The channel-blocking properties of arvanil may, at least in part, contribute to the underlying mechanisms by which it affects neuronal or neuroendocrine function.

Action Potentials↗

PubMed2004

Regulation of ion channel localization and phosphorylation by neuronal activity.

Voltage-dependent Kv2.1 K(+) channels, which mediate delayed rectifier Kv currents (I(K)), are expressed in large clusters on the somata and dendrites of principal pyramidal neurons, where they regulate neuronal excitability. Here we report activity-dependent changes in the localization and biophysical properties of Kv2.1. In the kainate model of continuous seizures in rat, we find a loss of Kv2.1 clustering in pyramidal neurons in vivo. Biochemical analysis of Kv2.1 in the brains of these rats shows a marked dephosphorylation of Kv2.1. In cultured rat hippocampal pyramidal neurons, glutamate stimulation rapidly causes dephosphorylation of Kv2.1, translocation of Kv2.1 from clusters to a more uniform localization, and a shift in the voltage-dependent activation of I(K). An influx of Ca(2+) leading to calcineurin activation is both necessary and sufficient for these effects. Our finding that neuronal activity modifies the phosphorylation state, localization and function of Kv2.1 suggests an important link between excitatory neurotransmission and the intrinsic excitability of pyramidal neurons.

Animals↗

PubMed2005

Phosphoinositide phosphatases: emerging roles as voltage sensors?

During a genomic survey of the transparent sea squirt (Ciona intestinalis), Murata et al. discovered a gene that encodes a protein containing homologous sequences to both a CX(5)R phosphatase and an ion channel. The authors named the novel protein, C. intestinalis voltage-sensor-containing phosphatase, Ci-VSP. The N terminus of Ci-VSP appears to function as a voltage-gated sensor; the C terminus functions as a phosphoinositide phosphatase. The authors suggest that when the N-terminal voltage sensor is activated, this in turn activates the phosphatase, which converts PI(3,4,5)P(3) to PI(4,5)P(2). Localized changes in membrane PI(4,5)P(2) levels could then serve to either positively or negatively regulate a variety of ion transporters and channels.

Animals↗

PubMed1996

Regulation of 4-aminopyridine-sensitive, delayed rectifier K+ channels in vascular smooth muscle by phosphorylation.

Voltage-gated, delayed rectifier K+ current (KV) that is sensitive to 4-aminopyridine (4AP) block has been identified in all vascular smooth muscle tissues studied to date. These channels conduct outward, hyperpolarizing K+ current that influences resting membrane potential and contributes to repolarization of action potentials. Smooth muscle cells in most arterial resistance vessels regulate Ca2+ influx and contractile tone by low amplitude, tonic changes in membrane potential. Block of KV with 4-aminopyridine leads to contraction and an enhanced myogenic response to increased intravascular pressure. We investigated the modulation of KV currents in isolated, freshly dispersed smooth muscle cells from rabbit portal vein and coronary arteries in whole-cell voltage clamp experiments. Our findings indicate that KV channels are regulated by signal transduction mechanisms involving vasoactive agonists that activate cAMP-dependent protein kinase (PKA) or protein kinase C (PKC). In this paper, the properties and potential function of KV channels in vascular smooth muscle are reviewed. Further, the regulation and potential role of alterations in KV due to beta-adrenoceptor agonists, adenylyl cyclase and PKA, as well as angiotensin II, diacylglycerol, and PKC are discussed.

4-Aminopyridine↗

PubMed2002

Hypoxic vasorelaxation inhibition by organ culture correlates with loss of Kv channels but not Ca(2+) channels.

We (Thorne GD, Shimizu S, and Paul RJ. Am J Physiol Cell Physiol 281: C24-C32, 2001) have recently shown that organ culture for 24 h specifically inhibits relaxation to acute hypoxia (95% N(2)-5% CO(2)) in the porcine coronary artery. Here we show similar results in the porcine carotid artery and the rat and mouse aorta. In the coronary artery, part of the inability to relax to hypoxia after organ culture is associated with a concomitant loss in ability to reduce intracellular Ca(2+) concentration ([Ca(2+)](i)) during hypoxia (Thorne GD, Shimizu S, and Paul RJ. Am J Physiol Cell Physiol 281: C24-C32, 2001). To elucidate the mechanisms responsible for the loss of relaxation to hypoxia, we investigated changes in K(+) and Ca(2+) channel activity and gene expression that play key roles in [Ca(2+)](i) regulation in vascular smooth muscle (VSM). Reduced mRNA expression of O(2)-sensitive K(+) channels (Kv1.5 and Kv2.1) was shown by reverse transcriptase-polymerase chain reaction in the rat aorta. In contrast, no change in other expressed voltage-gated K(+) channels (Kv1.2 and Kv1.3) or Ca(2+) channel subtypes was found. Modified K(+) channel expression is supported by functional evidence indicating a reduced response to general K(+) channel activation, by pinacidil, and to specific voltage-dependent K(+) (Kv) channel blockade by 4-aminopyridine. In conclusion, organ culture decreases expression of specific Kv channels. These changes are consistent with altered mechanisms of VSM contractility that may be involved in Ca(2+)-dependent pathways of hypoxia-induced vasodilation.

Animals↗

PubMed1998

Regulation of voltage-gated K+ channel expression in the developing mammalian myocardium.

As in neurons, depolarization-activated, Ca2+-independent outward K+ currents play prominent roles in shaping the waveforms of action potentials in myocardial cells. Several different types of voltage-gated K+ currents that contribute to the distinct phases of action potential repolarization have been characterized in myocardial cells isolated from different species, as well as in cells isolated from different regions of the heart in the same species. Important among these are the transient outward current, I(to), similar to the neuronal K+ current IA, and several components of delayed rectification, including I(Kr)[IK(rapid)], I(Ks)(IK(slow)], and I(Kur)[IK(ultrarapid)]. The properties of these currents in different species and cell types are remarkably similar, suggesting that the molecular correlates of functional voltage-gated K+ channel types are also the same. A number of voltage-gated K+ channel (Kv) pore-forming (alpha) and accessory (beta) subunits have now been cloned from heart cDNA libraries, and a variety of experimental approaches are being exploited to determine the molecular relationships between these subunits and functional voltage-gated myocardial K+ channels. Considerable progress has been made recently in defining these relationships, and the results obtained to date indeed suggest that distinct molecular entities underlie the different types of voltage-gated K+ channels characterized electrophysiologically in myocardial cells. Marked changes in the densities and/or the properties of voltage-gated K+ currents occur during normal cardiac development, as well as in conjunction with myocardial damage or disease, and there is considerable interest in understanding the molecular mechanisms underlying these changes. Although there is evidence for transcriptional, translational, and posttranslational regulation of functional voltage-gated K+ channel expression, we are only beginning to understand the underlying mechanisms; further studies focussed on delineating the molecular mechanisms controlling functional K+ channel expression are clearly warranted.

Animals↗

PubMed2001

Actions of arachidonic acid on contractions and associated electrical activity in guinea-pig isolated ventricular myocytes.

The actions of arachidonic acid (AA) were investigated in guinea-pig isolated ventricular myocytes. Exposure of myocytes to 10 microM AA reduced the amplitude of contractions and calcium transients accompanying action potentials at a frequency of 1 Hz. AA (10 microM) also reduced the amplitude of calcium currents recorded under voltage-clamp conditions. The suppression of contraction by AA was not prevented by either 10 microM trihydroindomethicin (to inhibit cyclo-oxygenase) or 10 microM ETYA (5,8,11,14-eicosatetraynoic acid, to inhibit AA metabolising enzymes), showing that the actions of AA appeared not to be mediated by these metabolites. The reduction of contraction by 10 microM AA was also not prevented by the protein kinase C inhibitor, Ro31-8220 (1 microM), showing that this pathway appeared not to be required for the observed effect. Direct effects of AA may be involved. A further action of 10 microM AA was to suppress spontaneous electrical activity induced by either the beta-adrenergic agonist isoprenaline or the Na(+) pump inhibitor, ouabain. This effect of AA on spontaneous activity might be associated with the observed reduction of calcium entry through L-type calcium channels, although additional effects of AA on calcium release from the sarcoplasmic reticulum might also be involved. Experimental Physiology (2001) 86.4, 437-449.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed2003

Effects of prostaglandin F2alpha on membrane currents in rabbit middle cerebral arterial smooth muscle cells.

Although PGF(2alpha) affects contractility of vascular smooth muscles, no studies to date have addressed the electrophysiological mechanism of this effect. The purpose of our investigation was to examine the direct effects of PGF(2alpha) on membrane potentials, Ca(2+)-activated K(+) (K(Ca)) channels, delayed rectifier K(+) (K(V)) channels, and L-type Ca(2+) channels with the patch-clamp technique in single rabbit middle cerebral arterial smooth muscle cells (SMCs). PGF(2alpha) significantly hyperpolarized membrane potentials and increased the amplitudes of total K(+) currents. PGF(2alpha) increased open-state probability but had little effect on the open and closed kinetics of K(Ca) channels. PGF(2alpha) increased the amplitudes of K(V) currents with a leftward shift of the activation and inactivation curves and a decrease in the activation time constant. PGF(2alpha) decreased the amplitudes of L-type Ca(2+) currents without any significant change in threshold or apparent reversal potentials. This study provides the first finding that the direct effects of PGF(2alpha) on middle cerebral arterial SMCs, at least in part, could attenuate vasoconstriction.

Animals↗

PubMed2000

Effect of hydrogen peroxide on the membrane currents of sinoatrial node cells from rabbit heart.

The effects of H(2)O(2) on pacemaker activity and underlying membrane currents were studied in isolated rabbit sinoatrial (SA) node cells using perforated patch current- and voltage-clamp methods. Short-term exposure (<10 min) of the nodal cells to H(2)O(2) (200 microM) resulted in an initial shortening of spontaneous action potential cycle length (from 445 +/- 60 to 398 +/- 56 ms; P < 0.05) and a prolongation of action potential duration. H(2)O(2) (100 microM) significantly increased peak L-type Ca(2+) current (I(Ca,L)) from -384 +/- 77 to -439 +/- 84 pA (116 +/- 2%, n = 6). Additionally, the persistent or non-inactivating component of I(Ca,L) was increased from -52 +/- 3 to -88 +/- 14 pA (174 +/- 19%, n = 6). The hyperpolarization-activated current (I(f)) was decreased from -228 +/- 62 to -161 +/- 72 pA after exposure to H(2)O(2) (n = 7). There were no changes in the delayed rectifier K(+) current (I(K)) (n = 7). H(2)O(2)-induced Ca(2+) currents were blocked by 2 microM nicardipine (n = 6), 2 mM Ni(2+) (n = 2), and the protein kinase C (PKC) inhibitor bisindolylmaleimide (10(-7) M; n = 4) but not by 20 microM tetrodotoxin. These results suggest that H(2)O(2) can increase the spontaneous pacing rate in rabbit SA node cells by enhancing I(Ca,L) and that this effect is mediated by a PKC-dependent pathway.

Action Potentials↗

PubMed2003

Influence of pore residues on permeation properties in the Kv2.1 potassium channel. Evidence for a selective functional interaction of K+ with the outer vestibule.

The Kv2.1 potassium channel contains a lysine in the outer vestibule (position 356) that markedly reduces open channel sensitivity to changes in external [K(+)]. To investigate the mechanism underlying this effect, we examined the influence of this outer vestibule lysine on three measures of K(+) and Na(+) permeation. Permeability ratio measurements, measurements of the lowest [K(+)] required for interaction with the selectivity filter, and measurements of macroscopic K(+) and Na(+) conductance, were all consistent with the same conclusion: that the outer vestibule lysine in Kv2.1 interferes with the ability of K(+) to enter or exit the extracellular side of the selectivity filter. In contrast to its influence on K(+) permeation properties, Lys 356 appeared to be without effect on Na(+) permeation. This suggests that Lys 356 limited K(+) flux by interfering with a selective K(+) binding site. Combined with permeation studies, results from additional mutagenesis near the external entrance to the selectivity filter indicated that this site was located external to, and independent from, the selectivity filter. Protonation of a naturally occurring histidine in the same outer vestibule location in the Kv1.5 potassium channel produced similar effects on K(+) permeation properties. Together, these results indicate that a selective, functional K(+) binding site (e.g., local energy minimum) exists in the outer vestibule of voltage-gated K(+) channels. We suggest that this site is the location of K(+) hydration/dehydration postulated to exist based on the structural studies of KcsA. Finally, neutralization of position 356 enhanced outward K(+) current magnitude, but did not influence the ability of internal K(+) to enter the pore. These data indicate that in Kv2.1, exit of K(+) from the selectivity filter, rather than entry of internal K(+) into the channel, limits outward current magnitude. We discuss the implications of these findings in relation to the structural basis of channel conductance in different K(+) channels.

Cell Line↗

PubMed2006

A computational analysis of central CO2 chemosensitivity in Helix aspersa.

We created a single-compartment computer model of a CO(2) chemosensory neuron using differential equations adapted from the Hodgkin-Huxley model and measurements of currents in CO(2) chemosensory neurons from Helix aspersa. We incorporated into the model two inward currents, a sodium current and a calcium current, three outward potassium currents, an A-type current (I(KA)), a delayed rectifier current (I(KDR)), a calcium-activated potassium current (I(KCa)), and a proton conductance found in invertebrate cells. All of the potassium channels were inhibited by reduced pH. We also included the pH regulatory process to mimic the effect of the sodium-hydrogen exchanger (NHE) described in these cells during hypercapnic stimulation. The model displayed chemosensory behavior (increased spike frequency during acid stimulation), and all three potassium channels participated in the chemosensory response and shaped the temporal characteristics of the response to acid stimulation. pH-dependent inhibition of I(KA) initiated the response to CO(2), but hypercapnic inhibition of I(KDR) and I(KCa) affected the duration of the excitatory response to hypercapnia. The presence or absence of NHE activity altered the chemosensory response over time and demonstrated the inadvisability of effective intracellular pH (pH(i)) regulation in cells designed to act as chemostats for acid-base regulation. The results of the model indicate that multiple channels contribute to CO(2) chemosensitivity, but the primary sensor is probably I(KA). pH(i) may be a sufficient chemosensory stimulus, but it may not be a necessary stimulus: either pH(i) or extracellular pH can be an effective stimuli if chemosensory neurons express appropriate pH-sensitive channels. The lack of pH(i) regulation is a key feature determining the neuronal activity of chemosensory cells over time, and the balanced lack of pH(i) regulation during hypercapnia probably depends on intracellular activation of pH(i) regulation but extracellular inhibition of pH(i) regulation. These general principles are applicable to all CO(2) chemosensory cells in vertebrate and invertebrate neurons.

Acid-Base Equilibrium↗

PubMed2000

Time-dependent block of the slowly activating delayed rectifier K(+) current by chromanol 293B in guinea-pig ventricular cells.

The slowly activating delayed rectifier K(+) current (I(Ks)) was recorded in single myocytes dissociated from guinea-pig ventricles and the mechanism underlying the block of I(Ks) by a chromanol derivative, 293B, was investigated. In the presence of 1 - 100 microM 293B, activation phase of I(Ks) was followed by a slower decay during 10 s depolarizing pulses. Both the rate and extent of the decay were increased in a concentration-dependent manner. The relationship between the concentration of 293B and the block showed a Hill's coefficient of approximately 1. The half-inhibitory concentration was approximately 3.0 microM and did not differ significantly at various membrane potentials from +20 to +80 mV. A mathematical model for the 293B block was constructed on the basis of multiple closed and open states for the I(Ks) channels, and the blocking rate was calculated by fitting the model to the original current traces. The blocking rate constant showed a linear function with the 293B concentration, indicating 1 : 1 binding stoichiometry. At +80 mV the blocking rate was 4x10(4) M(-1) s(-1) and the unblocking rate was 0.2 s(-1). The results indicate that 293B is an open channel blocker with relatively smaller blocking rate than those reported so far for time-dependent blockade of various ionic channels.

Algorithms↗