News Physiol Sci 14: 135-142, 1999;
1548-9213/99 $5.00
News in Physiological Sciences, Vol. 14, No. 4, 135-142,
August 1999
© 1999 Int. Union Physiol. Sci./Am. Physiol. Soc.
The ether-à-go-go-Related Gene K+ Current: Functions of a Strange Inward Rectifier
Jürgen R. Schwarz and
Christiane K. Bauer
J. R. Schwarz and C. K. Bauer are in the Abteilung für angewandte Physiologie, Physiologisches Institut, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, D-20246 Hamburg, Germany.
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Abstract
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The erg channels mediate an inward-rectifying K+ current because of their peculiar gating kinetics. They are involved in repolarization of the cardiac action potential, frequency adaptation, and maintenance of the resting potential. Reduction of erg currents via an intracellular signal cascade underlies the thyrotropin-releasing hormone-induced increase in prolactin secretion.
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Introduction
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Potassium ion (K+) channels comprise a large and heterogeneous group of ion channels. They are present in almost all animal and plant cells and are involved in various physiological functions. They can be subdivided according to their preferred direction of current flow into outward-rectifying and inward-rectifying K+ channels, as well as according to the different mechanisms by which they are activated. The K+ currents first described by Hodgkin and Huxley 50 years ago in their classical analysis of the ionic basis of the action potential of the squid giant axon are mediated by voltage-dependent outward-rectifying K+ (Kv) channels. They are closed at the resting potential and activated upon depolarization. The outward current flowing through this type of K+ channel is the main mechanism for the repolarization of action potentials in many excitable cells. In contrast, classical inward-rectifying K+ channels (Kir) are active at the normal resting potential and close upon depolarization.
A novel group within the increasing number of cloned Kv channels is the ether-à-go-go gene (EAG) family. The first member of this family was cloned from a mutant of the fruit fly, Drosophila melanogaster, which was characterized by a leg-shaking behavior when the flies were anesthetized with ether. Since 1994, different mammalian homologs of the Drosophila EAG channels have been cloned (14). Members of the EAG family were classified as Kv channels because they are K+ selective and are constructed by subunits with six putative membrane-spanning domains. It was soon recognized that EAG-mediated membrane currents exhibit distinct gating kinetics and pharmacological properties. On the basis of structural homologies, three different EAG subfamilies are distinguished: ether-à-go-go gene (eag), eag-like (elk), and eag-related gene (erg) K+ channels (Fig. 1A
). As yet, more EAG channels have been cloned and biophysically characterized in heterologous expression systems than have been identified in native tissue. Therefore, the native correlates and the physiological role of only a few of the cloned members of the EAG family are known. Among these, the functions of erg-mediated K+ currents have best been characterized in various native cells.
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Molecular biology of EAG K+ channels
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Like the other voltage-dependent K+ channels, EAG channels are composed of four subunits, each of which consists of six putative transmembrane-spanning domains (Fig. 1B
). Inward-rectifying Kir channels are also formed by four subunits, but each subunit consists of only two transmembrane domains, which are homologous to the S5 and S6 domains of the outward-rectifying K+ channels. Although still speculative, a more and more detailed picture of the functional significance of the structural components of K+ channels emerges (Fig. 1C; Refs. 8, 9). The inner channel wall seems to be constructed by the S5 and S6 segments together with the pore (P) region, which forms a loop between S5 and S6. In addition to being a part of the permeation pathway, the P region is involved in forming the K+ selectivity filter. The outer channel wall is presumably made by the S1 to S4 segments. In the S4 segment, every third amino acid carries a positive charge, suggesting that this structure is part of the voltage sensor. There are experimental indications that S4 is moved upon a depolarization in a screwlike manner to the external side (sliding-helix model) inducing complex, as yet unknown, structural changes leading to the opening of the channel. After they have been opened, most Kv channels are closed by inactivation. Inactivation can be brought about by a closure of the cytoplasmic mouth of the pore by the ball-like structure of the NH2-terminal (ball-and-chain mechanism). This type of inactivation is called N-type inactivation. In addition, there is an intrinsic inactivation (C-type inactivation) that can be altered after a mutation in the P region or S6 domain.
Within this general framework, there are only a few structural elements of EAG channels that distinguish them from the other Kv channels. The P region of EAG channels has a characteristic signature sequence (GFGN) that is different from that of other K+ channels (GYGD). Another typical structure of EAG channels is the presence of a cyclic nucleotide binding domain (cNBD) within the cytoplasmic part of the COOH-terminal (Fig. 1B). The significance of the EAG signature sequence and the function of the cNBD are not known.
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EAG currents have distinct biophysical properties
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After the cloning of mammalian homologs of the EAG channel family from a human hippocampal cDNA library, they were functionally expressed in heterologous expression systems. Studies on these channels clearly demonstrated that the gating kinetics, as well as other properties of the different subfamilies of the EAG K+ channels, are distinct from those of other K+ currents. Since then, three members of the elk subfamily, two members of the eag subfamily, and three members of the erg subfamily have been cloned. Within the eag and erg subfamilies the properties of the functionally expressed currents are qualitatively the same. The elk-mediated currents are more heterogeneous; the elk1 and elk3 currents are noninactivating like the eag current, whereas the elk2 current is a functional inward-rectifying K+ current like the erg current. The characteristics of eag and erg currents are described below.
The eag current. The eag K+ channels are activated by depolarization. The time course of current activation through eag channels is considerably slower than that of currents mediated by the Shaker-like Kv channels. The eag currents reach a steady-state amplitude without ensuing inactivation. Characteristically, activation of eag currents is slowed down by more negative prepulses or by an increase in the extracellular Mg2+ concentration. Furthermore, eag-mediated currents are blocked by a rise in the intracellular Ca2+ concentration ([Ca2+]i). Examples of an eag-like current in a native cell exhibiting the same properties as the heterologously expressed eag current have recently been described in neuroblastoma cells and photoreceptors.
The erg current. The typical current pattern mediated by erg channels is illustrated in Fig. 1D. In contrast to the classical delayed-rectifying K+ current, a large depolarizing potential induces a small transient outward current that quickly declines to a steady state. A large transient outward current is elicited only upon repolarization. This characteristic current phenomenology has been explained by assuming that erg K+ channels have inverse gating kinetics compared with classical Kv channels, i.e., their inactivation kinetics are faster than their activation kinetics and recovery from inactivation proceeds much faster than deactivation.
According to these distinct kinetics, the depolarizing pulse activates erg channels; however, as soon as they are activated, some of the channels immediately inactivate, explaining the small steady-state outward current. The large transient outward current upon repolarization is caused by fast recovery from inactivation with subsequent slow deactivation. It is this transient outward current that is functionally important for the fast repolarization of the cardiac action potential (see below). The peculiar gating kinetics of the native cardiac erg current was first postulated by Shibasaki in 1987 (12), long before the cloning of erg channels (14).
The erg channels can be selectively blocked by class III antiarrhythmic substances such as the methanesulfonanilides E-4031 and WAY-123,398. These substances are now used by many laboratories as pharmacological tools to isolate the erg-mediated current from other K+ currents in native cells and to investigate the functional role of these currents. The erg currents are also blocked by some neuroleptics like haloperidol and histamine-receptor antagonists like terfenadine. These pharmacological effects explain the serious cardiac side effects of these widely used therapeutic agents.
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The erg current contributes to repolarization of the cardiac action potential
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The best known example of an erg-mediated K+ current in a native tissue is the rapidly activating K+ current in the heart (IKr; Ref. 10). During the plateau phase of the cardiac action potential two different outward currents are activated, the rapidly (IKr) and the slowly (IKs) activating delayed-rectifying K+ currents. IKs is mediated by KvLQT1, a member of the KQT channel family, most probably coassembled with a ß-subunit (minK). IKr is mediated by erg K+ channels possibly also coassembled with minK. IKr has only a small outward current amplitude during the plateau phase of the action potential, thus supporting the formation of the plateau, which is a typical function of an inward rectifier. However, as repolarization proceeds, the characteristic gating kinetics of erg channels induce an increase in outward current (see Fig. 1D). This erg current, together with the activation of the classical cardiac inward rectifier (IK1), quickly repolarizes the action potential. The contribution of IKr to the cardiac action potential can be demonstrated by using erg channel-blocking class III antiarrhythmic substances. In Fig. 2A, the effect of blocking IKr with WAY-123,398 is shown. The duration of the cardiac action potential is increased without changing the other parameters of the action potential (13). A prolongation of the heart action potential is also induced by a mutation in the human ether-à-go-go-related gene (HERG). This inherited disease is characterized by a prolonged Q-T interval (LQT2 syndrome; Ref. 10. The functional consequence of this mutation is an increased tendency to cardiac arrhythmias and torsade de pointes, which eventually leads to sudden death. As an infrequently occuring serious side effect, similar symptoms occur during treatment of heart disease with class III antiarrhythmic agents that block IKr (11). In the heart, the effect of erg channels is restricted to repolarization because of the presence of the large inward-rectifying K current (IK1), which keeps the resting potential in myocytes so negative that erg K channels deactivate between the action potentials.
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FIGURE 2. Examples of different functions of the erg-mediated current. A: effect of a block of the erg current with the class III antiarrhythmic drug WAY-123,398 on the action potential recorded from a cat ventricular myocyte. The drug (0.3 µM) induced a pronounced prolongation of the action potential duration without affecting other components of the action potential (modified from Ref. 3). B: effect of WAY-123,398 on the repetitive activity of an F-11 dorsal root ganglion neuron x neuroblastoma hybrid cell. Injection of current (35 pA) from a holding potential of –70 mV elicited two action potentials in the control, whereas after a 2-min application of the drug ongoing repetitive activity was induced (modified from Ref. 6). C,a: increase in the electrical activity of a GH3/B6 cell after application of the class III antiarrhythmic E-4031 (from Ref. 15 with permission). C,b: recording of the membrane potential from a GH3/B6 cell. WAY-123,398 (10 µM) induced a depolarization of the membrane potential. Action potentials were blocked by NiCl2 and low Ca2+ (from Ref. 3 with permission).
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The erg current can induce frequency adaptation
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Spike frequency adaptation is a general property of cells capable of generating action potentials. After injection of a depolarizing current into an excitable cell, the evoked repetitive activity exhibits increasingly longer interspike intervals until no further action potential can be elicited. This phenomenon has been attributed to the activation of different types of K+ currents, such as the current mediating the afterhyperpolarization in hippocampal neurons (IAHP) or the M current. It has recently been shown in neuroblastoma cells that the erg-mediated K+ current can also induce spike frequency adaptation (6). In these cells, after a depolarization, the amplitude of the erg-mediated outward current slowly increases, thus counteracting the Na+ and Ca2+ inward currents. Frequency adaptation is induced because the number of activated erg channels slowly adds up during successive action potentials because of the slow time course of deactivation (see Fig. 1D). The interspike interval in neuroblastoma cells is too short to deactivate the erg current. Therefore, a frequency-dependent accumulation of erg outward current occurs during a train of action potentials. The involvement of the erg current in spike frequency adaptation has been demonstrated with the use of class III antiarrhythmics. After application of WAY-123,398, spike frequency adaptation is abolished (Fig. 2B).
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The resting potential is set by the erg-mediated current and correlated with different cellular functions
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Classical inward-rectifying Kir channels are predominantly involved in the maintenance of the resting potential. In muscle cells or neurons, the resting potential is between –60 and –80 mV. These negative potentials are achieved because classical inward rectifiers do not inactivate at negative potentials. Therefore, their small outward currents shift the membrane potential toward the K equilibrium potential. However, there are cells that are devoid of classical inward rectifier channels but possess erg channels. In these cells, the resting potential is mediated by the erg current and is therefore less negative because at membrane potentials more negative than about –50 mV, erg channels deactivate (see Figs. 1D and 3). Different examples are described below in which erg-like currents contribute to the resting potential and the resting potential is correlated to different cellular functions.
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FIGURE 3. The E-4031-sensitive native current of lactotrophs and the current mediated by the rat homolog of the HERG channel (rerg) are identical. A: isolation of the inward-rectifying K+ current (IK,ir) as an E-4031-sensitive current recorded in external 5 mM K+ solution in a GH3/B6 cell. a: Inward and outward membrane currents recorded from a GH3/B6 cell using the pulse protocol shown above the membrane currents. Holding potential was –20 mV. b: Membrane currents recorded from same cell as in a after addition of 10 µM E-4031. c: Isolation of IK,IR as the E-4031-sensitive current obtained by subtraction of the currents recorded in the presence of E-4031 from the control currents. d: Current-voltage (I-E) curve of peak and steady-state (measured at end of 200-ms test pulses) amplitudes of outward and inward E-4031-sensitive currents shown in c. B: membrane currents recorded in external 5 mM K+ solution in a CHO cell previously injected with rerg cDNA. a: Holding potential, –40 mV; membrane currents recorded at test potentials between 0 and –120 mV in steps of 10 mV. Depolarizing prepulses were applied to "fully activate" the erg K channels. b: I-E curve of peak and steady-state amplitudes of currents shown in a (modified from Refs. 3 and 4).
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In quail neural crest cells, erg K+ channels are transiently expressed during the immature stages of neural differentiation, whereas in later stages classical inward-rectifying K+ channels are present. This sequential expression of erg channels and classical inward rectifiers is mirrored by the sequential occurrence of two different levels of resting potentials. The low resting membrane potential during the immature stage is shifted to more negative values after differentiation (2). Under normal culture conditions, erg currents in neuroblastoma cells exhibit a large variability in voltage dependence that correlates with the values of the resting potential. After the cell cycle is synchronized with retinoic acid, the variability in the voltage dependence of erg channels and in the resting potential decreases (1). Further analysis will reveal to what degree these correlations reflect causal relationships.
In lactotrophs of the anterior pituitary, as in various other neuroendocrine cells, there is a strong coupling between excitability and hormone secretion (7). Prolactin secretion from lactotrophs is inhibited by dopamine and increased by thyrotropin-releasing hormone (TRH). The intracellular mechanisms underlying the TRH-induced signal cascade have been extensively studied in clonal rat pituitary cells (GH3 and the subclone GH3/B6; Ref. 7). GH3/B6 cells fire spontaneous action potentials that are carried by an influx of Ca2+ through voltage-dependent Ca2+ channels regulating the intracellular Ca2+ concentration ([Ca2+]i). Figure 2 shows that an erg-mediated K+ current contributes to the resting potential. Application of class III antiarrhythmics (E-4031 or WAY-123,398) depolarizes the membrane potential and increases the frequency of action potentials (Fig. 2C,a; see also Fig. 4A). In the absence of spontaneous activity, the depolarization of the membrane potential is clearly visible (Fig. 2C,b). As will be shown below, these electrophysiological changes mimic TRH effects associated with the late phase of the TRH-induced prolactin secretion.
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FIGURE 4. Summary of the cellular mechanisms underlying the biphasic thyrotropin-releasing hormone (TRH) response in GH3/B6 cells (see text). A: recording of the membrane potential of a GH3/B6 cell. Application of 500 nM TRH induced a biphasic electrical response comprised of a transient hyperpolarization and a subsequent increase in the frequency of action potentials. Application of 1 µM E-4031 induced an increase in the frequency of action potentials imitating the second phase of the TRH response. B: inward-rectifying K+ current recorded in a GH3/B6 cell. TRH induced a reduction of the erg-mediated outward current (elicited with a pulse to –40 mV) and inward current (elicited with a pulse to –100 mV), which are both completely blocked by 10 µM E-4031. Test pulses were preceded by a depolarizing pulse to +20 mV. Holding potential, –20 mV. Experiment performed in external 5 mM K+ solution. C: measurement of prolactin secretion from single lactotrophs with reverse hemolytic plaque assay (RHPA). Incubation of lactotrophs with E-4031 induces a shift in the frequency distribution to larger plaque areas. IP3, inositol 1,4,5-trisphosphate; Cav, voltage-dependent Ca2+ channels.
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The erg-mediated current can be isolated as the E-4031-sensitive current
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The essential properties of the erg-like inward-rectifying K+ current (IK,ir) present in lactotrophs were described long before it was possible to identify this current as an erg-mediated K+ current (5). With the use of class III antiarrhythmics like E-4031 it is now possible to isolate IK,ir, as the E-4031-sensitive current, from the other K+ currents present in these cells (Fig. 3A; Refs. 4, 15). Comparison of the gating kinetics of the native K+ current, isolated as the E-4031-sensitive current, with those of the erg current recorded after functional expression in a heterologous expression system (Fig. 3B) shows that the currents have identical properties. The erg currents were elicited from a depolarized membrane potential to "fully activate" the erg channels (12). Actually, the erg channels were partially inactivated. Nevertheless, large transient currents were recorded upon a subsequent hyperpolarization, as expected for fully activated channels, because recovery from inactivation is much faster than deactivation (Fig. 1D). The current-potential relationship of the peak and steady-state amplitudes of the E-4031-sensitive current clearly shows that the inward current is much larger than the outward current. The outward current has a maximum amplitude at about –40 mV, which correlates with the value of the resting potential in these cells. At more positive potentials the outward current decreases, indicating the decrease in the K+ conductance typical for an inward rectifier. IK,ir present in GH3/B6 cells is very similar to the erg-like current in lactotrophs from primary culture. Both currents exhibit biophysical and pharmacological properties that are almost the same as those of erg currents.
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TRH reduces the erg current
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The physiological function of the erg-like current in lactotrophs is illustrated in the current-clamp recording of Fig. 4A. The cell exhibited spontaneous firing of action potentials, and after application of TRH a classical biphasic response occurred consisting of a transient hyperpolarization followed by an increased firing of action potentials (7). The second phase lasted several minutes, and then the cell resumed its low firing rate. The subsequent block of the erg current with 1 µM E-4031 induced a depolarization and an increased firing of action potentials mimicking the second phase of the TRH response. Figure 4B shows that the TRH-induced increase in the frequency of action potentials is indeed caused by a reduction of the erg current by TRH, which reduces the inward as well as the small outward erg current. This reduction is mainly caused by a shift in the voltage dependence of the erg current to more positive potentials (5).
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Prolactin secretion from lactotrophs is controlled by modulation of the erg current
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The intracellular signal cascade leading to the TRH-induced increase in prolactin secretion in GH3/B6 cells is summarized in Fig. 4. After binding of TRH to its receptor in the plasma membrane, a biphasic cellular response is induced comprising changes in membrane potential (Fig. 4A), [Ca2+]i, and prolactin secretion. The intracellular signal cascade underlying the first phase of the TRH response consists of the binding of TRH to its receptor, activation of phospholipase C via a G protein of the Gq/11 family, and production of inositol trisphosphate (IP3) and diacylglycerol. IP3 induces release of Ca2+ from intracellular pools, leading to a transient increase in [Ca2+]i and the first phase of prolactin secretion. As an epiphenomenon, a transient hyperpolarization occurs because of the opening of Ca2+-dependent K+ channels. The second phase of the TRH response consists of a depolarization and an increase in the frequency of action potentials (Fig. 4A) mediated by the TRH-induced reduction of the erg current (Fig. 4B). These electrophysiological events induce an increased influx of Ca2+ through voltage-dependent Ca2+ channels, generating the plateau increase in [Ca2+]i and leading to the enhanced increase in prolactin secretion. As indicated in Fig. 4, the G protein as well as the further steps of the signal cascade leading to closure of the erg K+ channels are still unknown. Although it is very likely that a phosphorylation of erg K+ channels is involved, activation of protein kinases C and A seems not to be responsible for this effect (for review, see Ref. 7).
Evidence that the block of the erg current in lactotrophs leads to an increase in prolactin secretion is given by measurements with the reverse hemolytic plaque assay (Fig. 4C). Erythrocytes loaded with protein A are mixed with dissociated pituitary cells and transferred to culture dishes. During an incubation period, prolactin secreted from single lactotrophs binds to prolactin antibodies attached to the erythrocytes. Addition of complement induces hemolysis of those erythrocytes loaded with the antibody-prolactin complex. The plaque areas are a semiquantitative measure of prolactin secretion from the single lactotrophs. E-4031 enhances prolactin secretion due to an increase in the number of plaque-forming lactotrophs as well as to an increase in the amount of hormone secreted from the individual lactotrophs, as indicated by the shift of the frequency distribution to larger plaque areas (Fig. 4C). These data demonstrate the functional importance of the erg current in the TRH-induced increase in prolactin secretion. Until now, the underlying TRH-induced reduction of the erg current is the only physiological example of a modulation of an erg current by a neuromodulator or transmitter.
We have described the structure and function of erg K+ channels that form a subgroup of the novel EAG K+ channel family. As yet, the physiological importance of erg-mediated currents has been recognized in only a few native cells such as cardiac myocytes, neuroblastoma cells, and lactotroph cells. However, because erg RNA has been detected in various other tissues, erg-mediated K+ currents will probably be recorded in more native cells. Analysis of the relationship between structure and function has already started to reveal the molecular basis of the distinct kinetics and pharmacological properties of erg channels. This knowledge will also help in understanding the effects and side effects of many neuroleptics, histamine antagonists, and possibly other therapeutic substances.
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Introduction
Molecular biology of EAG...
-subunits consist of 6 membrane-spanning domains (S1–S6). A cyclic nucleotide binding domain (cNBD) is located in the COOH-terminal. C: proposed tetrameric structure of a functional K+ channel composed of 4