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PubMed2004

Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.

Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca2+ channels by activating G(i/o)-protein-coupled CB1 cannabinoid receptors (CB1R)--a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca2+ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca2+ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC50=2 nM)>2-AGE (350 nM) approximately 2-AG (480 nM)>AEA (approximately 3 microM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 microM) also inhibited Ca2+ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function.

Animals↗

PubMed2002

Characterization of Dir: a putative potassium inward rectifying channel in Drosophila.

Potassium channels vary in their function and regulation, yet they maintain a number of important features - they are involved in the control of potassium flow, cell volume, cell membrane resting potential, cell excitability and hormone release. The potassium (K(+)) inward rectifier (Kir) superfamily of channels are potassium selective channels, that are sensitive to the concentration of K(+) ions. They are termed inward rectifiers since they allow a much greater K(+) influx than efflux. There are at least seven subfamilies of Kir channels, grouped according to sequence and functional similarities (Curr. Opin. Neurobiol. 5 (1995) 268; Annu. Rev. Physiol. 59 (1997) 171). While numerous Kir channels have been discovered in a variety of organisms, Drosophila inward rectifier (Dir) is the first putative inward rectifier to be studied in Drosophila. In fact, there are only three genes (including Dir) encoding putative inward rectifiers in the Drosophila genome. Though there are other known potassium channels in Drosophila such as ether-a-go-go and shaker, most are voltage-gated channels. As an important first step in characterizing Kir channels in Drosophila, we initiated studies on Dir.

Amino Acid Sequence↗

PubMed2001

Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice.

G-Protein-coupled inwardly rectifying potassium channels (GIRKs) regulate synaptic transmission and neuronal firing rates. Selective enhancement of GIRK2 function by intoxicating concentrations of ethanol was recently shown for recombinant homomeric and heteromeric channels. We proposed that specific behavioral actions of ethanol are due to activation of GIRK channels and that these behaviors would be reduced or eliminated in GIRK2 null mutant ("knockout") mice. Three behavioral effects of ethanol were absent in mutant mice as compared with wild-type littermates: stimulation of home cage (habituated) motor activity, anxiolytic action in elevated-plus maze test, and handling-induced convulsions (HIC) after an acute injection of ethanol. In contrast to these reductions of ethanol action, mutant mice displayed greater ethanol-stimulated activity in peripheral regions of an open field. There were no differences between mutant and wild-type mice for ethanol-induced sleep time, acute functional tolerance, or HIC following chronic matched consumption of a liquid diet. Ethanol preference and consumption were equal for wild-type and mutant mice using the standard two-bottle choice test with alternation of the bottles. However, this test was complicated by the strong side preference of the mice. When ethanol was presented constantly in their favored location, the consumption of ethanol was substantially higher for mutant than for wild-type mice. In the absence of ethanol, GIRK2 knockout mice showed more motor activity, less anxiety, and higher HIC. These results provide evidence that GIRK2 channels mediate specific behaviors, including anxiety and convulsions, and may influence effects of ethanol on these behaviors.

Alcohol Drinking↗

PubMed2004

Inwardly rectifying potassium channels in rat retinal ganglion cells.

Inwardly rectifying potassium channels (Kir channels) are important for neuronal signalling and membrane excitability. In the present work we characterized, for the first time, Kir channels in rat retinal ganglion cells (RGCs), the output neurons in the retina, using immunocytochemical and patch-clamp techniques. Various subunits of Kir channels (Kir1.1, 2.1, 2.3, 3.1, 3.2 and 3.3) were expressed in RGCs, but with distinct subcellular localization. Kir1.1 was mainly expressed in axons of RGCs. Kir2.1 and Kir2.3 were both present in somata of RGCs. Whereas staining for Kir3.1 was profoundly present in an endoplasmic reticulum-like structure and Kir3.2 was strongly expressed in the cytoplasm and the cytomembrane of somata, dendrites and axons of RGCs, faint, sparse labelling for Kir3.3 was seen in the cytomembrane. Immunoreactivity for Kir4.1 and Kir4.2 was not detectable in RGCs. Whole-cell currents mediated by Kir channels were recorded in isolated RGCs and they differed from hyperpolarization-activated currents (I(h)) by showing full activation in < 10 ms, no inactivation, and being significantly suppressed by 300 microM Ba2+. Unlike in retinal horizontal cells and bipolar cells, these currents were mainly mediated by G-protein-coupled Kir3 (GIRK) channels, as demonstrated by the fact that GDP(beta)S and GTP(gamma)S included in the pipette solution markedly decreased and increased the currents, respectively. Furthermore, the GIRK channels were probably coupled to GABA(B) receptors, because baclofen considerably increased the Kir currents and the increased currents were suppressed by Ba2+. These characteristics of the Kir currents provide more versatility for signalling of RGCs.

Animals↗

PubMed2000

Functional evidence for inward-rectifier potassium channels in rat cremaster muscle arterioles.

Moderate increases in extracellular K(+) produce vasodilation in fourth order cremasteric arterioles in the anesthetized rat. We studied the contribution of different subtypes of K(+) channels to this response. Cremaster muscle arteriolar diameters were observed during superfusion with buffer containing 5-30 mM K(+) in the absence (control) and presence of barium (Ba(2+), 50 microM), glibenclamide (GLIB, 1 microM), or iberiotoxin (IBTX, 100 nM) to block inward-rectifier, ATP-sensitive, or Ca(2+)-activated K(+) channels, respectively. Under control conditions, vessels dilated in response to 10-25 mM K(+) and constricted at higher concentrations. At 5 mM K(+), vessel diameters were significantly decreased by GLIB and Ba(2+), but not IBTX, suggesting that basal diameter was regulated by inward-rectifier and ATP-sensitive K(+) channels. In contrast, Ba(2+), but not GLIB or IBTX, prevented K(+)-induced dilation. The data indicate that the inward-rectifier K(+) channel (blocked by low concentrations of Ba(2+), but not GLIB or IBTX) was most likely responsible for the K(+)-induced arteriolar dilation.

Adenosine↗

PubMed2001

G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics.

G protein-gated inwardly rectifying potassium channels (GIRKs) are a family of homo- and hetero-oligomeric K(+) channels composed of different subunits (GIRK1 to 4 in mammals). GIRK4 and GIRK1 are found mainly in the atrium, whereas neuronal cells predominantly express the GIRK1, GIRK2, and GIRK3 isoforms. When activated, GIRK channels slow the firing rate of atrial myocytes and neuronal cells. Because of their key role in controlling excitability, we investigated the influence of a prototypic anesthetic, halothane, on GIRK channels of different subunit composition expressed in Xenopus laevis oocytes. Halothane enhanced background currents through hetero-oligomeric GIRK1/GIRK4 and homo-oligomeric GIRK1(F137S) channels but not through homo-oligomeric GIRK2 channels. This activation of basal current did not depend on the presence of coexpressed G protein-coupled receptors but instead required the presence of G(beta/gamma). In contrast to basal GIRK currents, the agonist-induced GIRK current (via coexpressed m2 muscarinic receptors) was inhibited by halothane. For GIRK1/GIRK4 and GIRK1(F137S) channels this inhibition was most pronounced at low concentrations of the anesthetic (0.1-0.3 mM) and occurred also when channels had been activated by guanosine-5'-O-(3-thio)triphosphate. This inhibition, however, was overridden by high concentrations of halothane (0.9 mM) and augmentation of the agonist-induced current was observed. This increase in agonist-induced current was never seen with GIRK2 homo-oligomeric channels. Agonist-induced currents mediated by GIRK2 channels were always inhibited by halothane with an IC(50) value of approximately 60 microM. These data suggest a direct interaction of halothane with GIRK channels.

Anesthetics, Inhalation↗

PubMed2005

Differential distribution of individual subunits of strongly inwardly rectifying potassium channels (Kir2 family) in rat brain.

Inwardly rectifying potassium (Kir) channels modulate cellular excitability, membrane potential, and secretion of neurotransmitters and hormones. Kir channels with the strongest inward rectification belong to the Kir2 family. In this report, polyclonal monospecific affinity-purified antibodies against the less conserved carboxy-terminal sequences of Kir2.1, Kir2.2, Kir2.3, and Kir2.4 were used to analyze the detailed distribution of all members of the Kir2 family in the rat central nervous system. Kir2 channel expression is detected in neurons but not in glial cells. Kir2 protein distribution confirms the basic mRNA localization pattern given by in situ hybridization. Kir2.1 is detected throughout the whole brain but in particular subsets of neurons with highest expression in olfactory bulb and superior colliculus. Kir2.2 immunoreactivity is primarily displayed in several forebrain nuclei, hypothalamus, cerebellum, and spinal cord. The Kir2.3 subunit is predominantly localized in olfactory bulb, basal ganglia, cortex, and cerebellar Purkinje cells. In contrast, Kir2.4-positive staining is detected at significantly lower levels in most neurons throughout the rat brain with highest expression in brainstem motoneurons. Thus, our data show a more widespread distribution of Kir2.4 than previously determined. In summary, the widespread presence of all four Kir2 channel subunits in the rat brain provides further evidence for their important role in central signal processing and neural transmission.

Animals↗

PubMed1999

Expression of adenosine triphosphate-sensitive potassium channel subunits in female rat reproductive tissues: overlapping distribution of messenger ribonucleic acid for weak inwardly rectifying potassium channel subunit 6.1 and sulfonylurea-binding regulatory subunit 2.

OBJECTIVE: Potassium channel activation has been shown to decrease uterine tone and is a target for inhibition of uterine activity in the treatment of preterm labor. In addition, potassium channel activation also appears to be involved in oocyte maturation. The specific potassium channels responsible for these channel currents have not been identified but are known to be responsive to such agents as pinacidil and to be inhibited by glibenclamide. These findings suggest the presence of an adenosine triphosphate-sensitive potassium channel that is a complex of a weak inwardly rectifying potassium channel subunit 6.1 or 6.2 and sulfonylurea-binding regulatory subunit 1 or 2. STUDY DESIGN: The technique of reverse transcriptase-polymerase chain reaction was used to detect the presence of messenger ribonucleic acid for sulfonylurea-binding regulatory subunit 1 and 2 and weak inwardly rectifying potassium channel subunit 6.1 and 6.2 in the ovary and myometrium of the pregnant rat. In situ hybridization histochemical analysis was used to identify the specific cell types expressing each messenger ribonucleic acid. RESULTS: Reverse transcriptase-polymerase chain reaction analysis found expression of messenger ribonucleic acid for sulfonylurea-binding regulatory subunits 1 and 2B and messenger ribonucleic acid for weak inwardly rectifying potassium channel subunit 6.1 in rat myometrium and ovary during gestation. There was no evidence for expression of weak inwardly rectifying potassium channel subunit 6.2 messenger ribonucleic acid in the ovary or the myometrium of the pregnant rat. In situ hybridization histochemical examination localized expression of messenger ribonucleic acid for sulfonylurea-binding regulatory subunit 2B and messenger ribonucleic acid for weak inwardly rectifying potassium channel subunit 6.1 to uterine myocytes and granulosa cells of the corpus luteum. The cells expressing sulfonylurea-binding regulatory subunit 1 messenger ribonucleic acid could not be identified because of the scarcity of this messenger ribonucleic acid. Messenger ribonucleic acid for sulfonylurea-binding regulatory subunit 1, messenger ribonucleic acid for sulfonylurea-binding regulatory subunit 2B, and messenger ribonucleic acid for weak inwardly rectifying potassium channel subunit 6.1 were also observed in the placenta by in situ hybridization histochemical examination. CONCLUSION: The results suggest that the major adenosine triphosphate-sensitive potassium channel expressed in the myometrium and the corpus luteum during pregnancy is a complex of sulfonylurea-binding regulatory subunit 2B and weak inwardly rectifying potassium channel subunit 6.1.

ATP-Binding Cassette Transporters↗

PubMed1998

Expression of two inward rectifier potassium channels is essential for differentiation of primitive human hematopoietic progenitor cells.

A potassium inward rectifier (K(ir)) current was previously shown by us to be induced in primitive hematopoietic progenitor cells, stimulated with the combination of interleukin-3 (IL-3) and stem cell factor (SCF). Biophysical features of whole cell currents implicated the involvement of more than one K(ir) channel type. Employing IL-3 + SCF stimulated human cord blood CD34+38- cells, we isolated and characterized different components of this current. Reverse transcription-polymerase chain reaction (RT-PCR) subcloning identified the expression of a strongly rectifying K(ir) channel (K(ir) 4.3) as well as a weakly rectifying K(ir) channel (K(ir) 1.1) in these cells. Inhibition of the expression of each of the channels suppressed progenitor cell generation by IL-3 and SCF-stimulated CD34+38- cells in 7-day suspension cultures. The variable expression of two essential inward rectifying potassium channels early in the course of hematopoietic progenitor cell differentiation may play a potentially important role in potassium homeostasis in these cells.

ADP-ribosyl Cyclase↗

PubMed2003

Altered mRNA expression of ATP-sensitive and inward rectifier potassium channel subunits in streptozotocin-induced diabetic rat heart and aorta.

Cardiovascular diseases are the most frequent and costly complication of diabetes. Many previous studies showed that ATP-sensitive potassium channels (K(ATP)) and inward rectifier potassium channels (Kir) play important regulatory roles in functions of cardiovascular tissues. It's still not very clear how these potassium channels are involved in cardiovascular complications of diabetes. We used the streptozotocin (STZ)-induced diabetic rats model to study the expressions of K(ATP) and Kir channel subtypes in diabetic cardiovascular tissues. The mRNA expression levels of Kir2.1, Kir3.1, Kir6.1, Kir6.2, and sulfonylurea receptor (SUR) 2A and 2B subunits in heart and aortal smooth muscles were determined by the reverse-transcription polymerase chain reaction. The results showed that in comparison with the control rats, mRNA expression of SUR 2A was reduced significantly in the diabetic heart (SUR 2A/GAPDH, 1.04 +/- 0.16 vs 0.38 +/- 0.09, P<0.01, n = 3); SUR 2B was reduced markedly in the aortal smooth muscle of diabetic rats (SUR 2B/GAPDH, 1.13 +/- 0.14 vs 0.35 +/- 0.07, P<0.01, n = 3). However, there are no significant expression changes of Kir2.1, Kir3.1, Kir6.1, and Kir6.2 in diabetic rats. These results suggested that expression of specific K(ATP) channel subunits were altered in the heart and aorta of diabetic rats.

Adenosine Triphosphate↗

PubMed1994

Molecular cloning, functional expression and localization of a novel inward rectifier potassium channel in the rat brain.

We have cloned a novel inward rectifier potassium channel from a rat brain cDNA library and designated it RB-IRK2. The rat brain cDNA library was screened using a fragment of the mouse macrophage IRK1 cDNA as a probe. The amino acid sequence of RB-IRK2 shares 70%, 40% and 45% identity to mouse IRK1, rat ROMK1 and rat GIRK1, respectively. Xenopus oocytes injected with cRNA derived from RB-IRK2 expressed a potassium current which showed inward-rectifying channel characteristics similar to the IRK1 current, but distinct from the ROMK1 or the GIRK1 currents. However, the localization of RB-IRK2 mRNA in rat tissues, assessed by the Northern blot analysis, differed from that of mouse IRK1. These results indicate that the IRK family is composed of multiple genes, which express in different tissues and therefore may play heterogenous functional roles in various organs, including rat central nervous system.

Amino Acid Sequence↗

PubMed1998

P2Y receptor subtypes differentially couple to inwardly-rectifying potassium channels.

Subtypes of P2Y receptors are well characterized with respect to their agonist profile but little is known about differences in their intracellular signalling properties. When expressed in Xenopus oocytes, both P2Y2 and P2Y6 receptors effectively couple to endogenous Ca2+-dependent Cl--channels. However, only P2Y2 receptors increased currents mediated by inward-rectifier K+ channels of the Kir3.0 subfamily. This increase in Kir-current was sensitive to pertussis toxin, while activation of Ca2+-dependent Cl--channels was not. In contrast, suramin, a P2 receptor antagonist, inhibited activation of both channels. These observations suggest that, in contrast to P2Y6, P2Y2 receptors couple to two different classes of G proteins.

Adenosine Triphosphate↗

PubMed1996

Acute effects of thyroid hormone on inward rectifier potassium channel currents in guinea pig ventricular myocytes.

Thyroid hormones play an important role in cardiac electrophysiology. However, the regulation of cardiac ionic channels by thyroid hormones is still unclear. To evaluate the acute effect of 3,3',5-triiode-L-thyronine (T3) on inward rectifier potassium channel (IK1) action potentials, whole-cell IK1 currents and steady-state single IK1 currents were recorded in guinea pig ventricular myocytes. Acute exposure of cells to T3 resulted in shortening of the action potential durations. This effect was initiated at 5-15 min and reached a stable plateau at 25 min. The amplitude of steady-state whole-cell IK1 was significantly increased by T3 at 1 nM to 1 microM concentration rage and with ED50 12 nM/liter. T3 (1 microM) increased IK1 by 68 +/- 7% at -40 mV and 52 +/- 9% at -100 mV. Similar effects were observed with triiodothyroacetic acid, an analogue of T3 that does not stimulate DNA transcription. The single IK1 open probability (Po) was increased 7 +/- 1% by 1 nM T3 (n = 9, P < 0.05) and 42 +/- 6% by 1 microM T3 at -40 mV (n = 18, P < 0.0001). However, the channel unit amplitude, time constants of open and fast-closed time were not changed. T3 shortened interburst duration at each membrane potential but did not change the burst behavior. To elucidate detailed mechanism, we assumed a three-state model (C1 <==> C2 <==> O) and calculated each rate constant. T3 significantly increased the rate constant, k+1, for the transition from the C1 to the C2 state at RP -40 mV (2.84 +/- 0.56 to 7.28 +/- 1.23 sec-1, P < 0.01), RP -20 mV (3.63 +/- 0.95 to 10.17 +/- 2.60 sec-1, P < 0.05) and RP (6.73 +/- 1.20 to 21.94 +/- 4.49 sec-1, P < 0.01). However, the other rate constants were not affected. These results demonstrate that T3 enhances IK1 with the increment in Po, which mainly results from shortening of interburst duration without any changes in burst behavior. Hence, the shortening of interburst duration is due to acceleration of the transition from the C1 to the C2 state. The enhanced IK1 by T3 might be one of the causes for shortened action potential duration in hyperthyroidism.

Action Potentials↗

PubMed2001

Targeting of an A kinase-anchoring protein, AKAP79, to an inwardly rectifying potassium channel, Kir2.1.

Protein kinase A (PKA) is targeted to discrete subcellular locations close to its intended substrates through interaction with A kinase-anchoring proteins (AKAPs). Ion channels represent a diverse and important group of kinase substrates, and it has been shown that membrane targeting of PKA through association with AKAPs facilitates PKA-mediated phosphorylation and regulation of several classes of ion channel. Here, we investigate the effect of AKAP79, a membrane-associated multivalent-anchoring protein, upon the function and modulation of the strong inwardly rectifying potassium channel, Kir2.1. Functionally, the presence of AKAP79 enhanced the response of Kir2.1 to elevated intracellular cAMP, suggesting a requirement for a pool of PKA anchored close to the channel. Antibodies directed against a hemagglutinin epitope tag on Kir2.1 coimmunoprecipitated AKAP79, indicating that the two proteins exist together in a complex within intact cells. In support of this, glutathione S-transferase fusion proteins of both the intracellular N and C domains of Kir2.1 isolated AKAP79 from cell lysates, while glutathione S-transferase alone failed to interact with AKAP79. Together, these findings suggest that AKAP79 associates directly with the Kir2.1 ion channel and may serve to anchor kinase enzymes in close proximity to key channel phosphorylation sites.

A Kinase Anchor Proteins↗

PubMed2004

Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes.

Dystroglycan (DG) is part of a multiprotein complex that links the extracellular matrix to the actin cytoskeleton of muscle fibers and that is involved in aggregating acetylcholine receptors at the neuromuscular junction. This complex is also expressed in regions of the central nervous system where it is localized to both neuronal and glial cells. DG and the inwardly rectifying potassium channels, Kir4.1, are concentrated at the interface of astroglia and small blood vessels. These channels are involved in siphoning potassium released into the extracellular space after neuronal excitation. This raises the possibility that DG may be involved in targeting Kir4.1 channels to specific domains of astroglia. To address this question, we used mixed hippocampal cultures to investigate the distribution of DG, syntrophin, dystrobrevin, and Kir4.1 channels, as well as aquaporin-permeable water channels, AQP4. These proteins exhibit a similar distribution pattern and form aggregates in astrocytes cultured on laminin. Both DG and syntrophin colocalize with Kir4.1 channel aggregates in astrocytes. Similarly, DG colocalizes with AQP4 channel aggregates. Quantitative studies show a significant increase of Kir4.1 and AQP4 channel aggregates in astrocytes cultured in the presence of laminin when compared with those in the absence of laminin. These findings show that laminin has a role in Kir4.1 and AQP4 channel aggregation and suggest that this may be mediated via a dystroglycan-containing complex. This study reveals a novel functional role for DG in brain including K+ buffering and water homeostasis.

Animals↗

PubMed1995

Three distinct structural environments of a transmembrane domain in the inwardly rectifying potassium channel ROMK1 defined by perturbation.

To probe the protein environment of an ion channel, we have perturbed the structure of a transmembrane domain by substituting side chains with those of two different sizes by using site-specific mutagenesis. We have used Trp and Ala as a high- and a low-impact perturbation probe, respectively, to replace each of 18 consecutive residues within the putative second transmembrane segment, M2, of an inwardly rectifying potassium channel, ROMK1. Our rationale is that a change in the channel function as a consequence of these mutations at a particular position will reflect the structural environment of the altered side chain. Each position can then be assigned to one of three classes of environments, as grated by different levels of perturbation: very tolerant (channel functions with both Trp and Ala substitutions), tolerant (function preserved with Ala but not with Trp substitution), and intolerant (either Ala or Trp substitution destroys function). We identify the very tolerant environment as being lipid-facing, tolerant as protein-interior-facing, and intolerant as pore-facing. We observe a strikingly ordered pattern of perturbation of all three environmental classes. This result indicates that M2 is a straight alpha-helix.

Alanine↗

PubMed2003

Surface expression of inward rectifier potassium channels is controlled by selective Golgi export.

Traffic of integral membrane proteins along the secretory pathway is not simply a default process but can be selective. Such selectivity is achieved by sequence information within the cargo protein that recruits coat protein complexes to drive the formation of transport vesicles. A number of sequence motifs have been identified in the cytoplasmic domains of ion channels that regulate early trafficking events between the endoplasmic reticulum and the Golgi complex. Here, we demonstrate that the following trafficking step from the Golgi compartment to the plasma membrane can also be selective. The N-terminal domain of the inward rectifier potassium channel Kir2.1 contains specific sequence information that is necessary for its efficient export from the Golgi complex. Lack of this information results in accumulation of the protein within the Golgi and a significant decrease in cell surface expression. As similar results were obtained for the N terminus of another Kir channel subfamily member, Kir4.1, which could functionally substitute for the Kir2.1 N terminus, we propose a more general role of the identified N-terminal domains for post-Golgi trafficking of Kir channels.

Amino Acid Sequence↗

PubMed2004

Differential subunit composition of the G protein-activated inward-rectifier potassium channel during cardiac development.

Parasympathetic slowing of the heart rate is predominantly mediated by acetylcholine-dependent activation of the G protein-gated potassium (K+) channel (IK,ACh). This channel is composed of 2 inward-rectifier K+ (Kir) channel subunits, Kir3.1 and Kir3.4, that display distinct functional properties. Here we show that subunit composition of IK,ACh changes during embryonic development. At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit. This change in subunit composition results in reduced rectification of IK,ACh, allowing for marked K+ currents over the whole physiological voltage range. As a consequence, IK,ACh is able to generate the membrane hyperpolarization that underlies the strong negative chronotropy occurring in late- but not early-stage atrial cardiomyocytes upon application of muscarinic agonists. Both strong negative chronotropy and membrane hyperpolarization can be induced in early-stage cardiomyocytes by viral overexpression of the mildly rectifying Kir3.4 subunit. Thus, a switch in subunit composition is used to adopt IK,ACh to its functional role in adult cardiomyocytes.

Acetylcholine↗