The K<sup>+</sup> channel inward rectifier subunits form a channel similar to neuronal G protein‐gated K<sup>+</sup> channel

Velimirovic, Bratislav M.; Gordon, Eric A.; Lim, Nancy; Navarro, Betsy; Clapham, David E.

doi:10.1016/0014-5793(95)01465-9

Cited by 85 publications

(69 citation statements)

References 27 publications

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“…1 B-F). [GIRK channels are heterotetramers (16)(17)(18); therefore, when a mutant GIRK1 is tested, GIRK2(wt) was also transfected.] Compared with the large inward rectifying currents generated by GIRK2(wt)͞GIRK1(wt) channels, currents generated by the mutants, GIRK2(E315A)͞ GIRK1(wt) and GIRK1(E304A)͞GIRK2(wt), were reduced to 12% and 6%, respectively ( Fig.…”

Section: Mutation Of Girk2 E315 To Alanine and The Corresponding Mutamentioning

confidence: 99%

“…This alternative explanation does not agree with the constancy of the single-channel properties among various mutants ( Table 1). Homomultimers of GIRK2 produce short-duration ''spiky'' channels (16)(17)(18). Table 1 indicates the proportion of the short-duration component (a f ) was not altered by any of the C-terminus mutations of GIRKs.…”

Section: Mutant Girk2(e315a) Interacts With G␤␥mentioning

confidence: 99%

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A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome

Chen

Kawano

Bajic

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled inward rectifiers (GIRKs) are activated directly by G protein ␤␥ subunits, whereas classical inward rectifiers (IRKs) are constitutively active. We found that a glutamate residue of GIRK2 (E315), located on a hydrophobic domain of the C terminus, is crucial for the channel activation. This glutamate (or aspartate) residue is conserved in all members of the Kir family. Substitution of alanine for the glutamate on GIRK1, GIRK2, and IRK2, expressed in HEK293 cells, greatly reduced the whole-cell currents. The whole-cell current of GIRK channels with a constitutively active gate, GIRK2 (

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Section: Mutation Of Girk2 E315 To Alanine and The Corresponding Mutamentioning

confidence: 99%

Section: Mutant Girk2(e315a) Interacts With G␤␥mentioning

confidence: 99%

A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome

Chen

Kawano

Bajic

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on multiple expression studies and because Kir3.4 mRNA has been detected in only a few neuron populations, neuronal Kir3 channels are thought to be formed primarily by various combinations of Kir3.1, Kir3.2, and Kir3.3 subunits (Chen et al, 1997;Dascal, 1997;Isomoto et al, 1997;Karschin et al, 1996;Wickman et al, 2000). Although Kir3 channels formed by different combinations of Kir3 subunits generally exhibit similar functional properties, it should be noted that Kir3.1 homomultimeric complexes do not form functional channels Duprat et al, 1995;Hedin et al, 1996;Jelacic et al, 2000Jelacic et al, , 1999Krapivinsky et al, 1995a, b;Velimirovic et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Decreased Cocaine Self-Administration in Kir3 Potassium Channel Subunit Knockout Mice

Morgan

Carroll

Loth

et al. 2002

Neuropsychopharmacol

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Multiple G protein-linked neurotransmitter systems have been implicated in the behavioral effects of cocaine. While actions of certain neurotransmitter receptor subtypes and transporters have been identified, the role of individual G protein-regulated enzymes and ion channels in the effects of cocaine remains unclear. Here, we assessed the contribution of G protein-gated, inwardly rectifying potassium (Kir3/GIRK) channels to the locomotor-stimulatory and reinforcing effects of cocaine using knockout mice lacking one or both of the key neuronal channel subunits, Kir3.2 and Kir3.3. Cocaine-stimulated increases in horizontal locomotor activity in wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.2/3.3 double knockout mice, with only minor differences observed between the mouse lines. In contrast, Kir3.2 and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over a range of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than either single knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.

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“…[31][32][33] GIRK channels are tetrameric complexes formed by the variable assembly of 4 subunits (GIRK1-4). 34-37 While GIRK2, GIRK3, and GIRK4 can form functional homomultimeric channels, [34][35][36]38,39 GIRK1 requires assembly with either GIRK2, GIRK3, and/or GIRK4 to achieve surface membrane expression. 38,40 The G␤␥ subunits of pertussis toxin-sensitive (G i/o ) G proteins directly bind and activate GIRK channels.…”

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confidence: 99%

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

Shankar

Murugappan²,

Kim³

et al. 2004

Blood

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The role of the G i -coupled platelet P2Y 12 receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to ␣IIb␤3 activation in human platelets has not been delineated. As the P2Y 12 receptor has been shown to activate G protein-gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y 12 receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390 (R(؉)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(؎)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)-, 2-methylthioADP (2-MeSADP)-, U46619-, and low-dose thrombin-mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y 12 -mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced G qmediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y 12 receptor-selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y 12 receptor. We conclude that GIRK channels are important functional effectors of the P2Y 12 receptor in human platelets. IntroductionPlatelets play an important role in normal hemostasis and abnormal activation of platelets leads to thrombosis. During vascular injury or conditions of high shear, exposure of the collagen-rich subendothelium activates the platelets and results in the formation of a stable thrombus due to the combined action of adenosine diphosphate (ADP) secreted from platelet-dense granules and generated thrombin. 1 Any perturbations in this system can have pathologic cardiovascular implications such as intravascular thrombus formation and vascular occlusion.ADP is an important component of the platelet-dense granules and also an important platelet agonist that stimulates platelets by acting on the G q -coupled P2Y 1 receptor and G i -coupled P2Y 12 receptor. 2,3 Once released, it amplifies the primary responses of other agonists such as collagen and thrombin, leading to enhanced platelet aggregation and stability of the thrombus. 4,5 It is now well established that concomitant signaling through G q -coupled P2Y 1 and G i -coupled P2Y 12 is necessary and sufficient for the integrin GPIIb/IIIa activation. 3 Furthermore, selective G i activation, when coupled with selective G 12/13 stimulation, also results in platelet aggregation. 6,7 Notably, the P2Y 12 -coupled G i signaling is also crucial for potentiating dense...

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The K⁺ channel inward rectifier subunits form a channel similar to neuronal G protein‐gated K⁺ channel

Cited by 85 publications

References 27 publications

A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome

A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome

Decreased Cocaine Self-Administration in Kir3 Potassium Channel Subunit Knockout Mice

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

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The K+ channel inward rectifier subunits form a channel similar to neuronal G protein‐gated K+ channel

Cited by 85 publications

References 27 publications

A glutamate residue at the C terminus regulates activity of inward rectifier K + channels: Implication for Andersen's syndrome

A glutamate residue at the C terminus regulates activity of inward rectifier K + channels: Implication for Andersen's syndrome

Decreased Cocaine Self-Administration in Kir3 Potassium Channel Subunit Knockout Mice

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

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The K⁺ channel inward rectifier subunits form a channel similar to neuronal G protein‐gated K⁺ channel

A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome

A glutamate residue at the C terminus regulates activity of inward rectifier K ⁺ channels: Implication for Andersen's syndrome