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PubMed1996

Ca(2+)-dependent non-selective cation and potassium channels activated by bradykinin in pig coronary artery endothelial cells.

1. Using the cell-attached and inside-out modes of the patch-clamp technique, we studied the Ca(2+)-dependent ionic channels activated by bradykinin in cultured pig coronary artery endothelial cells to further understand electrophysiological events underlying cellular activation. 2. In the cell-attached mode, bradykinin (94 nM) activated two types of Ca(2+)-dependent channels: a high conductance K+ channel (285 pS in high symmetrical K+), whose open state probability was increased by depolarization, and a lower conductance inwardly rectifying non-selective cation channel (44 pS in high symmetrical K+). 3. The 285 pS K+ channel was half-maximally activated by cytosolic Ca2+ levels of 1.6 and 4.5 microM at +10 and -30 mV, respectively. Such local concentrations should be reached in the presence of bradykinin, which induces a mean maximal cytosolic Ca2+ rise of 1.3 microM. 4. The 285 pS K+ channel was inhibited by d-tubocurarine, which acted by reducing the mean open time duration (flickering pattern), finally reducing the channel conductance. 5. Divalent cations such as Ca2+ could flow through the 44 pS non-selective cation channel, with nearly the same permeability (P) as monovalent cations (PK: PNa: PCa = 1:1:0.7). 6. The cation channel appeared to be more sensitive to Ca2+ than the K+ channel, with a half-maximal open probability induced by 0.7 microM Ca2+ on the intracellular side of the membrane. 7. In contrast to the K+ channel, the cation channel mean open time was clearly increased by bradykinin. This effect was delayed compared with the increase in the channel open state probability and was rapidly lost in the inside-out configuration. Caffeine also activated the cation channel but more transiently than bradykinin and without any effect on the open duration. 8. In the absence of extracellular Ca2+, the bradykinin-induced increase in cytosolic free Ca2+ was shortened temporally by 52% and reduced in amplitude by 88%, whereas the bradykinin-induced hyperpolarization was not significantly reduced in amplitude but was shortened by 70%, thus illustrating the major role of Ca2+ influx in endothelial cell activation by bradykinin. 9. We conclude that bradykinin activates two types of Ca(2+)-dependent channels in coronary endothelial cells: a high conductance K+ channel regulated by membrane potential, and an inwardly rectifying cation channel allowing Ca2+ entry, the cation channel being about 6 times more sensitive to Ca2+ than the K+ channel. The increase in cation channel open state probability involves an increase in open number, like the K+ channel, but also involves a rise in channel open duration. Ca2+ entry via cation channels could contribute to increase the cytoplasmic Ca2+ level, activate Ca(2+)-dependent K+ channels, thus triggering membrane hyperpolarization when the endothelial cell is stimulated by a vasoactive agonist such as bradykinin.

Animals↗

PubMed2005

Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac KATP channels.

ATP-sensitive K+ (K(ATP)) channels are hetero-octamers of inwardly rectifying K+ channel (Kir6.2) and sulphonylurea receptor subunits (SUR1 in pancreatic beta-cells, SUR2A in heart). Heterozygous gain-of-function mutations in Kir6.2 cause neonatal diabetes, which may be accompanied by epilepsy and developmental delay. However, despite the importance of K(ATP) channels in the heart, patients have no obvious cardiac problems. We examined the effects of adenine nucleotides on K(ATP) channels containing wild-type or mutant (Q52R, R201H) Kir6.2 plus either SUR1 or SUR2A. In the absence of Mg2+, both mutations reduced ATP inhibition of SUR1- and SUR2A-containing channels to similar extents, but when Mg2+ was present ATP blocked mutant channels containing SUR1 much less than SUR2A channels. Mg-nucleotide activation of SUR1, but not SUR2A, channels was markedly increased by the R201H mutation. Both mutations also increased resting whole-cell K(ATP) currents through heterozygous SUR1-containing channels to a greater extent than for heterozygous SUR2A-containing channels. The greater ATP inhibition of mutant Kir6.2/SUR2A than of Kir6.2/SUR1 can explain why gain-of-function Kir6.2 mutations manifest effects in brain and beta-cells but not in the heart.

ATP-Binding Cassette Transporters↗

PubMed1993

Single-channel and whole-cell recordings from on-neurone glial cells in Helix pomatia ganglia.

A procedure is described for performing patch-clamp recordings on satellite glial cells kept in place within the nervous ganglia in the mollusc Helix. Glial cell properties were deduced from whole-cell and cell-attached recordings. The glial membrane was found to contain densely packed inwardly rectifying K+ channels. Activation of the neurones, under either current-clamp or voltage-clamp conditions, depolarized the glial cell layer wrapped around the neurones and induced a delayed persistent increase in the K+ channel opening probability. These results suggest that the glial channels opened in response to a signal emanating from the active neurones. This preparation provides a useful means of detecting and analysing neurone-glial interactions at the cell and unitary channel levels.

Animals↗

PubMed1989

Characterization of three types of potassium current in cultured neurones of rat supraoptic nucleus area.

1. Whole-cell, voltage-clamp recordings were obtained from neurones of the supraoptic area of neonatal rats in dissociated cell culture. Recordings were made from neurones having the same morphology as those which were vasopressin or oxytocin immunoreactive. 2. Three types of voltage-activated K+ current were identified on the basis of their kinetics, voltage sensitivities, Ca2+ dependence and pharmacology. The currents corresponded to the delayed rectifier current (IK), the A-current (IA), and the Ca2+-dependent current (IK(Ca] described in other neurones. 3. IK had a threshold of -40 mV, a sigmoidal time course of activation, and was sustained during voltage steps lasting less than 300 ms. The underlying conductance was voltage dependent reaching a maximum at +30 mV (mean maximum conductance 4.09 nS). The activation time constant was also voltage dependent declining exponentially from 4.5 ms at -30 mV to 1.8 ms at +50 mV. 4. IA was transient, and was activated from holding potentials negative to -70 mV; the maximum conductance (mean 5.9 nS) underlying the current was obtained at +10 mV. The activation and inactivation time constants were voltage dependent: the activation time constant declined exponentially between -40 mV (2.2 ms) and +40 mV (0.65 ms). 5. IK and IA were attenuated by the K+ channel blockers tetraethylammonium (TEA) and 4-aminopyridine (4-AP). TEA blocked the conductance underlying IK but appeared to alter the kinetics of IA. In contrast, 4-AP blocked the conductance underlying IA and, to a lesser extent, IK. 6. IK and IA were activated independently of external Ca2+ and the voltage activation of Ca2+ channels since these currents were recorded in the presence of Co2+, a Ca2+ channel blocker. 7. IK(Ca) was recorded only when Ca2+ (2 mM) was present in the external medium. From a holding potential of -30 mV, IK(Ca) had a threshold of -20 mV, was maximal at about +20 mV and declined at more positive potentials. This current was sustained during voltage steps lasting 100 ms and was abolished by addition of Co2+ (2 mM) to the medium. 8. The possible roles of the three K+ currents in regulating the characteristic firing behaviour of supraoptic neurones previously recorded in vivo and in vitro are discussed.

4-Aminopyridine↗

PubMed1999

Background leak K+-currents and oxygen sensing in carotid body type 1 cells.

One model of oxygen sensing by the carotid body is that hypoxia depolarises type 1 cells leading to voltage-gated calcium entry and the secretion of neurotransmitters which then excite afferent nerves. This paper revues the mechanisms responsible for the membrane depolarisation in response to hypoxia. It concludes that depolarisation is caused not through the inhibition of calcium activated or delayed rectifier K+-channels but through the inhibition of an entirely new type of background K+-channel. This channel lacks sensitivity to the classical K+-channel inhibitors TEA and 4-AP. New evidence does however reveal that background K+-channels in the type 1 cell can be inhibited by Ba2+ and that Ba2+ depolarises isolated type 1 cells. Intriguingly, Ba2+ is the only K+-channel inhibitor thus far reported to stimulate the carotid body. These studies therefore support the hypothesis that depolarisation of the type 1 cell is an integral part of the oxygen sensing pathway in the carotid body.

Animals↗

PubMed1996

Complement factor C5a and epidermal growth factor trigger the activation of outward potassium currents in cultured murine microglia.

Microglia, the resident macrophages of the brain, are transformed from a quiescent into an activated phenotype in a number of pathological conditions. The signalling mechanisms which control such transformations are not yet understood. In the present study, we have characterized fast electrophysiological responses in cultured microglia, induced by two putative signalling substances, complement 5a (C5a), a chemotactic agent for macrophages and microglia, and epidermal growth factor, the receptor of which is up-regulated during pathological conditions in the brain. Both factors transiently activate an outwardly rectifying K+ conductance, while the membrane of the unstimulated microglial cell is dominated by an inwardly rectifying K+ conductance. The C5a-stimulated current developed within about 20s and decayed within a slightly slower time course. It was activated by depolarlizing voltage steps positive to the resting membrane potential of about -70 mV, and neither inactivated nor showed a delayed activation following voltage steps. The epidermal growth factor-stimulated current showed similar characteristics. When G-proteins were specifically blocked, the K+ conductance could no longer be activated by C5a or epidermal growth factor, suggesting that for both agonists an inhibitory G-protein is involved in the intracellular signalling cascade. We tested if the induction of the K+ conductance is causally linked to other C5a-induced cellular responses, like transient cytosolic Ca2+ elevation and mobility. The K+ conductance was not activated when a Ca2+ transient was induced by thapsigargin, nor did a blockade of the C5a-induced K+ conductance by K+ channel blockers affect the motility response. This implies that after activation of the C5a receptor and the G-protein, the K+ conductance activation, the Ca2+ mobilization and the motility response are governed by independent intracellular pathways, and that the K+ conductance increase must serve other functions than the control of motility.

Animals↗

PubMed2001

Dofetilide block involves interactions with open and inactivated states of HERG channels.

Rapidly activating delayed rectifier current ( IKr) is the key target of class III antiarrhythmic drugs including dofetilide. Due to its complex gating properties, the precise channel state or states that interact with these agents remain poorly defined. We have undertaken a careful analysis of the state dependence of HERG channel block by dofetilide in Xenopus oocytes and Chinese Hamster Ovary (CHO) cells by devising a protocol in which brief sampling pulses were superimposed over a wide range of test potentials. The rate of block onset, maximal steady-state block and IC50 were similar for all test potentials over the activation range, demonstrating that the drug probably interacts with open and/or inactivated but not resting HERG channels with high affinity. Reducing the fraction of inactivated channels at 0 mV by augmenting the external potassium concentration did not alter the sensitivity to dofetilide. In contrast, the S631A and S620T HERG mutations both eliminated inward rectification and reduced dofetilide affinity by approximately 10- and approximately 100-fold respectively. We have also found a novel ultra-slow activation process which occurs in wild type HERG channels at threshold potentials. Overall, our data imply that dofetilide block occurs equally at all voltages positive to the activation threshold, and that the drug interacts with HERG channels in both the open and inactivated states.

Animals↗

PubMed1995

Effects of myosin light chain kinase inhibitors on delayed rectifier potassium current in bullfrog sympathetic neurons.

Actions of myosin light chain kinase inhibitors were tested on delayed rectifier potassium current (IK) in dissociated bullfrog sympathetic neurons. A microbial product, wortmannin (10 microM, extracellularly) and a synthetic peptide, SM-1 (20 microM, intracellularly) caused approximately 35 mV hyperpolarizing shift of the inactivation curve. Substitution of ATP (1.15 mM) in the pipette solution with 5'-adenylylimidodiphosphate mimicked the actions of wortmannin and SM-1. Results suggest that phosphorylation of myosin may modulate kinetics for the inactivation of IK.

Adenylyl Imidodiphosphate↗

PubMed1997

Effects of elevating [Na]i on membrane currents of canine ventricular myocytes: role of intracellular Ca ions.

OBJECTIVES: Our first objective was to study how elevating [Na]i can modify the background membrane conductance in canine ventricular myocytes (CVM). In particular, we wanted to find evidence for a Nai-activated K current (IK,Na) in these cells. The second objective was to compare the effects of elevating [Na]i on membrane currents without and with intracellular Ca buffering. METHODS: Whole-cell currents were recorded and [Na]i was elevated either by using a pipette perfusion device that allowed [Na] in the pipette solution to be varied (from 0 to 50 mM), or by 50 microM ouabain. RESULTS: Although an outward current attributable to IK,Na was confirmed in guinea-pig ventricular myocytes (GPVM) under our recording conditions, no such current was seen in 29 CVM examined. With Cai buffering, the main effect of elevating [Na]i on CVM was an increase in inward current around and negative to the resting membrane potential. Based on the dependence of this Nai-induced inward current on K ions and its pharmacological properties, especially the effects of low concentrations of external Ba ions (< or = 5 microM) at strongly hyperpolarized voltages, we hypothesize that this current was carried by extracellular K ions through the inward rectifier (IK1) channels that had been modified by the high level of [Na]i. With Cai buffering, elevating [Na]i by ouabain had few or no effects on the L-type Ca channel current (ICa) or the slow delayed rectifier current (IKs). Without Cai buffering, ouabain induced a rapid reduction of both currents along with an increase in a time-independent outward current at voltages positive to -60 mV. CONCLUSION: Our data suggest that there are species variations in K channel expression and/or K channel modulation by intracellular Na ions. Furthermore, intracellular Ca ions play a crucial role in mediating the effects of Nai loading on membrane currents in canine ventricular myocytes.

Animals↗

PubMed2004

Functional maturation of isolated neural progenitor cells from the adult rat hippocampus.

Although neural progenitor cells (NPCs) may provide a source of new neurons to alleviate neural trauma, little is known about their electrical properties as they differentiate. We have previously shown that single NPCs from the adult rat hippocampus can be cloned in the presence of heparan sulphate chains purified from the hippocampus, and that these cells can be pushed into a proliferative phenotype with the mitogen FGF2 [Chipperfield, H., Bedi, K.S., Cool, S.M. & Nurcombe, V. (2002) Int. J. Dev. Biol., 46, 661-670]. In this study, the active and passive electrical properties of both undifferentiated and differentiated adult hippocampal NPCs, from 0 to 12 days in vitro as single-cell preparations, were investigated. Sparsely plated, undifferentiated NPCs had a resting membrane potential of approximately -90 mV and were electrically inexcitable. In > 70%, ATP and benzoylbenzoyl-ATP evoked an inward current and membrane depolarization, whereas acetylcholine, noradrenaline, glutamate and GABA had no detectable effect. In Fura-2-loaded undifferentiated NPCs, ATP and benzoylbenzoyl-ATP evoked a transient increase in the intracellular free Ca(2+) concentration, which was dependent on extracellular Ca(2+) and was inhibited reversibly by pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS), a P2 receptor antagonist. After differentiation, NPC-derived neurons became electrically excitable, expressing voltage-dependent TTX-sensitive Na(+) channels, low- and high-voltage-activated Ca(2+) channels and delayed-rectifier K(+) channels. Differentiated cells also possessed functional glutamate, GABA, glycine and purinergic (P2X) receptors. Appearance of voltage-dependent and ligand-gated ion channels appears to be an important early step in the differentiation of NPCs.

Animals↗

PubMed1987

Effects of nicorandil on electromechanical activity of frog atrial muscle.

The effects of the antianginal drug nicorandil on electrical and mechanical activity of bullfrog atria were examined. The application of nicorandil at concentrations from 0.3 to 10 mM caused a negative inotropic effect without any appreciable change in the resting membrane potential. The amplitude of action potentials was attenuated. In the voltage clamp experiments, the slow inward current was slightly inhibited, but the background inward current and delayed outward current were not affected in the presence of nicorandil. The inward rectifying properties of time-independent outward current were slightly inhibited by 10 mM nicorandil. Nicorandil inhibited the caffeine-induced contractures elicited in the depolarized preparation, but had no effect on the contracture mediated through the Na-Ca exchange mechanism. These results suggest that the negative inotropic action of nicorandil is caused by inhibition of Ca influx and intracellular mobilization of Ca. Nicorandil had little effect on the potassium conductance in this preparation.

Animals↗

PubMed1990

Voltage-dependent currents in isolated cells of the frog retinal pigment epithelium.

1. Retinal pigment epithelial (RPE) cells were isolated enzymatically from bullfrog retinae. The patch-clamp technique was employed to investigate whole-cell currents under voltage-clamp conditions. 2. Isolated RPE cells were columnar or cuboidal in form, often with long processes protruding from the apical surface. Distinct apical and basal membrane domains were maintained for several hours following isolation. 3. The mean membrane capacitance was 62 pF. The resting potential averaged -30 mV, but it was as high as -75 mV in some cells. 4. Three voltage-dependent currents were observed: a time-independent and inwardly rectifying current and two time-dependent outwardly rectifying currents that had distinct kinetic properties. 5. Voltage pulses from a holding potential of -70 mV to potentials ranging from -30 to -120 mV produced membrane currents that were essentially time independent. The I-V relationship in this voltage range depended on the resting potential. It was usually inwardly rectifying in cells with resting potentials negative to about -50 mV, but tended to be linear in cells with more positive potentials. Three observations strongly suggested that the inwardly rectifying current is carried by K+. First, increasing the extracellular K+ concentration [( K+]) from 2 to 112 mM shifted the zero-current potential of the I-V relationship in the positive direction from an average value of -60 mV to 0 mV. Second, the addition of the K+ channel blockers Ba2+ (2 mM) or Cs+ (5 mM) to the extracellular solution inhibited a major component of the inwardly rectifying current. Finally, the reversal potential (Vr) of the Ba2(+)-sensitive current averaged -90 mV, near the K+ equilibrium potential (EK). 6. In approximately 50% of the cells, depolarizing voltage pulses to potentials more negative than -30 mV evoked an outward current that resembled the delayed rectifier present in other non-excitable cells. It activated with sigmoidal kinetics in less than 100 ms following a brief delay and then declined exponentially with a time constant of approximately 1 s. The peak chord conductance associated with this current was half-maximal at +14 mV. Several observations indicated that this outwardly rectifying current is carried primarily by K+: its Vr closely matched EK over a wide range of extracellular [K+]; it was inhibited 80% by exposure to the K+ channel blockers 4-aminopyridine (1 mM) and tetraethylammonium (20 mM); and it was abolished by intracellular dialysis with a K(+)-free solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Interleukin 1beta modulates rat subfornical organ neurons as a result of activation of a non-selective cationic conductance.

The circumventricular organs (CVOs) are ideal locations at which circulating pyrogens may act to communicate with the CNS during an immune challenge. Their dense vasculature and fenestrated capillaries allow direct access of these pyrogens to CNS tissue without impediment of the blood-brain barrier (BBB). One such CVO, the subfornical organ (SFO), has been implicated as a site at which the circulating endogenous pyrogen interleukin 1beta (IL-1beta) acts to initiate the febrile response. This study was designed to determine the response of rat SFO neurons to IL-1beta (1 nM to 100 fM) using whole-cell current-clamp and voltage-damp techniques. We found that physiological(subseptic) concentrations of IL-1beta (1 pM, 500 fM, 100 fm) induced a transient depolarization in SFO neurons accompanied by a significant increase in spike frequency. In contrast,pharmacological (septic) concentrations of IL-1beta (1 nM) evoked a sustained hyperpolarization. While depolarizations in response to IL-1beta were abolished by treatment of cells with the IL-1 receptor antagonist (IL-1ra), hyperpolarizations were still observed. Voltage-clamp analysis revealed that the majority (85 %) of SFO neurons responding to IL-1beta with depolarization (29 of 34 cells) exhibited an electrophysiological profile characterized by a dominant delayed rectifier potassium current (DIK), a conductance that we also found to be reduced to 84.4 +/- 3.3 % of control by bath application of IL-1beta. In addition, using slow voltage ramps we demonstrated that IL-1beta activates a non-selective cationic current (INSC) with a reversal potential of -38.8 +/- 1.8 mV. These studies identify the cellular mechanisms through which IL-1beta can influence the excitability of SFO neurons and, as a consequence of such actions, initiate the febrile response to exogenous pyrogens.

Action Potentials↗

PubMed1990

Anticholinergic action of quinidine sulfate in the rabbit atrioventricular node.

Anticholinergic action of quinidine sulfate was electrophysiologically studied by recording spontaneous action potentials and membrane current of the rabbit atrioventricular node. In the presence of 0.1 mumol/l carbachol, the spontaneous activity of the atrioventricular nodal preparations was markedly inhibited, whereas subsequent addition of 1, 5 and 20 mumol/l quinidine restored automaticity in a concentration-dependent manner. In some preparations, quinidine at concentrations of 5 mumol/l and higher slowed the spontaneous activity by its direct membrane action even in the presence of carbachol. The dose-response curve for acetylcholine action on the spontaneous firing frequency showed that one molecule of acetylcholine bound to one muscarinic receptor of the atrioventricular node cell (Hill coefficient = 1.2). A parallel shift of this curve towards higher acetylcholine concentrations was observed at 0.03, 0.1 and 0.3 mumol/l but not at 1 and 3 mumol/l quinidine, suggesting a noncompetitive antagonism of quinidine against acetylcholine. Voltage clamp experiments revealed that 5 mumol/l quinidine reduced the slow inward current, hyperpolarization-activated inward current, and delayed rectifying K+ current, through its membrane actions. Quinidine at this concentration almost completely suppressed the acetylcholine-activated K+ current, which showed a relaxation phenomenon. Hence, the direct blockage of the acetylcholine-activated K+ current by quinidine was considered responsible for the anticholinergic action of this drug. We conclude that quinidine is a non-specific ionic channel blocker that inhibits all the membrane currents in the atrioventricular node including the acetylcholine-activated K+ current.

Action Potentials↗

PubMed2001

Functional expression of a GFP-tagged Kv1.5 alpha-subunit in mouse ventricle.

The experiments here were undertaken to determine the feasibility of increasing the cell surface expression of voltage-gated ion channels in cardiac cells in vivo and to explore the functional consequences of ectopic channel expression. Transgenic mice expressing a green fluorescent protein (GFP)-tagged, voltage-gated K+ (Kv) channel alpha-subunit, Kv1.5-GFP, driven by the cardiac-specific alpha-MHC promoter, were generated. In recent studies, Kv1.5 has been shown to encode the micromolar 4-aminopyridine (4-AP)-sensitive delayed rectifier K+ current (I(K,slow)) in mouse myocardium. Unexpectedly, Kv1.5-GFP expression is heterogeneous in the ventricles of these animals. Although no electrocardiographic abnormalities were evident, expression of Kv1.5-GFP results in marked decreases in action potential durations in GFP-positive ventricular myocytes. In voltage-clamp recordings from GFP-positive ventricular myocytes, peak outward K+ currents are significantly higher, and their waveforms are distinct from those recorded from wild-type cells. Pharmacological experiments revealed a selective increase in a micromolar 4-AP-sensitive current, similar to the 4-AP-sensitive component of I(K,slow) in wild-type cells. The inactivation rate of the "overexpressed" current, however, is significantly slower than the Kv1.5-encoded component of I(K,slow) in wild-type cells, suggesting differences in association with accessory subunits and/or posttranslational processing.

Action Potentials↗

PubMed1992

Modulation of the delayed rectifier, IK, by cadmium in cat ventricular myocytes.

The effects of cadmium on the delayed outward potassium current (IK) were investigated in isolated cat ventricular myocytes using the single suction pipette voltage-clamp technique. IK activation was examined using peak tail currents elicited after 750-ms voltage-clamp steps to selected membrane potentials from a holding potential of -40 mV. In the presence of Cd2+ (0.2 mM), peak tail currents increased from a control value of 85 +/- 12 to 125 +/- 18 pA (n = 4). Activation curves constructed from the average peak tail-current measurements in all experiments showed that Cd2+ shifted the voltage dependence of activation to more positive potentials by 16.4 +/- 2.0 mV and increased the slope factor of the activation curve from 6.1 +/- 0.2 to 6.9 +/- 0.2 mV. In the absence of Cd2+, increases in holding potential from -30 to -70 mV had no effect on the magnitude of the peak tail currents, suggesting that the Cd(2+)-induced increase was not the result of a voltage-dependent increase in the number of available K+ channels at the holding potential. Slow voltage ramps from -70 to +70 mV revealed that Cd2+ increased the outward current at membrane potentials positive to +20 mV and shifted the voltage range in which IK inwardly rectified to more positive potentials. The fully activated current-voltage relationship was also shifted to more positive potentials by Cd2+. Cd2+ did not alter channel selectivity for K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart.

Repolarization of the cardiac action potential varies widely throughout the heart. This could be due to the differential distribution of ion channels responsible for repolarization, especially the K+ channels. We have therefore studied the cardiac localization of ERG, a channel protein known to play an important role in generation of the rapid component of the delayed rectifier K+ current (IKr), an important determinant of the repolarization waveform, Cryosections of the ferret atrium and ventricle were prepared to determine the localization of ERG by fluorescence in situ hybridization (FISH) and immunofluorescence. We found that in the ferret, ERG transcript and protein expression was most abundant in the epicardial cell layers throughout most of the ventricle, except at the base. In the atrium, we found that ERG is most abundant in the medial right atrium, especially in the trabeculae and the crista terminalis of the right atrial appendage. It also is present in areas within the sinoatrial node. In all regions studied, FISH and immunofluorescence showed concordant localization patterns. These data suggest that repolarization mediated by IKr is not uniform throughout the ferret heart and provide a molecular explanation for heterogeneity in action potential repolarization throughout the mammalian heart.

Action Potentials↗

PubMed1997

Membrane responses to extracellular ATP in rat isolated white adipocytes.

We used whole-cell and perforated-patch voltage-clamp methods to study the membrane electrical properties of isolated rat epididymal and inguinal white adipocytes. We examined cells from both Sprague-Dawley and Zucker lean and Zucker obese (fa/fa) rats. A delayed-rectifier potassium current was present and similar in unstimulated white fat cells from all these sources. The potassium current activated rapidly with depolarization positive to about -30 mV and showed slow inactivation. Stimulation with extracellular ATP activated both hyperpolarizing and depolarizing conductances. ATP exposure also increased cell membrane capacitance by an average of 16%, suggesting that ATP activates exocytosis. Exposure to norepinephrine had little electrophysiological effect. We conclude that white adipocytes are very similar to brown adipocytes in their resting electrophysiological profile and in their responses to extracellular ATP.

Adenosine Triphosphate↗