Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

doi:10.1038/sj.npp.1300484

Cited by 82 publications

(74 citation statements)

References 74 publications

(84 reference statements)

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“…Kir channels allow K + ions to enter the cells much more readily than does K + permeation in the outward direction (Kubo et al, 1993a). In the hK solution used to readily analyze Kir currents by enhancing the magnitude of currents, the K + equilibrium potential (E K ) was close to 0 mV, and inward K + current flow through GIRK channels was observed at negative holding potentials, as shown in previous studies (Dascal et al, 1993;Lewohl et al, 1999;Kobayashi et al, 2004b). For examining the effect of intracellular ifenprodil, 23 nl of 10 mM ifenprodil or 30 mM lidocaine N-ethyl bromide (QX-314) dissolved in distilled water was administered to an oocyte through an additional pipette by pressure injection using a Nanoliter injector (World Precision Instruments, Sarasota, FL, USA) as described previously , and the oocyte currents were then continuously recorded for approximately 30-40 min.…”

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confidence: 51%

“…The current responses were abolished in the presence of 3 mM Ba 2 + , which blocks the Kir channel family including GIRK channels (n ¼ 3). The 3 mM Ba 2 + -sensitive current components in oocytes expressing GIRK channels are considered to correspond to the magnitudes of GIRK1/2 currents (Kobayashi et al, 2004b). In uninjected oocytes, ifenprodil, even at the highest concentration used, or 3 mM Ba 2 + caused no significant response ( Figure 1c; n ¼ 4), suggesting no effect of ifenprodil or Ba 2 + on intrinsic oocyte channels.…”

Section: Inhibition Of Girk Channels By Ifenprodilmentioning

confidence: 99%

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Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Ifenprodil

Kobayashi

Washiyama

Ikeda

2005

Neuropsychopharmacol

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G protein-activated inwardly rectifying K + channels (GIRK, also known as Kir3) are regulated by various G-protein-coupled receptors. Activation of GIRK channels plays an important role in reducing neuronal excitability in most brain regions and the heart rate. Ifenprodil, which is a clinically used cerebral vasodilator, interacts with several receptors, such as a 1 adrenergic, N-methyl-D-aspartate, serotonin and s receptors. However, the molecular mechanisms underlying the various clinically related effects of ifenprodil remain to be clarified. Here, we examined the effects of ifenprodil on GIRK channels by using Xenopus oocyte expression assays. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, ifenprodil reversibly reduced inward currents through the basal GIRK activity. The inhibition was concentration-dependent, but voltage-and time-independent, suggesting that ifenprodil may not act as an open channel blocker of the channels. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to ifenprodil. Furthermore, GIRK current responses activated by the cloned k-opioid receptor were similarly inhibited by ifenprodil. The inhibitory effects of ifenprodil were not observed when ifenprodil was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated ifenprodil, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of ifenprodil. Our results suggest that direct inhibition of GIRK channels by ifenprodil, at submicromolar concentrations or more, may contribute to some of its therapeutic effects and adverse side effects.

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confidence: 51%

Section: Inhibition Of Girk Channels By Ifenprodilmentioning

confidence: 99%

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Ifenprodil

Kobayashi

Washiyama

Ikeda

2005

Neuropsychopharmacol

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“…Thus, alcoholinduced changes in affinity of GIRK for PIP 2 may recapitulate some of the same events induced by Gβγ binding. The cross-talk between alcohol, Gβγ, and the low affinity for PIP 2 suggest that GIRK channels have evolved to be sensitive to small molecules that either inhibit (48,49) or activate (3-5) the channel.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism underlying ethanol activation of G-protein–gated inwardly rectifying potassium channels

Bodhinathan

Slesinger

2013

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

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Alcohol (ethanol) produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. Here we used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate. Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gβγ subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcoholsensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction.A lcohol (ethanol) produces a wide range of pharmacological effects on the nervous system, ranging from anxiolytic effects to intoxication and alcohol addiction in certain individuals. Although the neural circuits underlying such addictive disorders are becoming better understood (1, 2), little is known about the molecular mechanisms underlying ethanol's interaction with specific target proteins, such as ion channels. G-proteingated inwardly rectifying K + (GIRK or Kir3) channels are activated by concentrations of ethanol relevant to human consumption (18 mM ethanol or 0.08% blood alcohol level) (3-5) and have been found to play a key role in alcohol-related disorders (6-9). For example, mice lacking GIRK2 (or Kir3.2) channels self-administer more ethanol and fail to develop conditioned place preference for ethanol, compared with wild-type (WT) littermates (6, 10). These results support a model in which ethanol may have lost its target in GIRK knockout mice, thus failing to elicit behaviors associated with ethanol consumption. Receptor activation of GIRK channels generates an outward, slow inhibitory postsynaptic current, which reduces neuronal activity (11). In addition to directly activating GIRKs, ethanol potentiates the slow inhibitory postsynaptic potential in midbrain dopamine neurons of the ventral tegmental area (8), which is produced by GABA B receptor activation of GIRK channels (7,12,13). Together these observations implicate GIRK channels in the etiology of alcohol dependence and addiction; however, the molecular details underlying ethanol activation of GIRK channels remain unknown.A major challenge is to understand how ethanol, with its simple chemistry of only two carbons and a hydroxyl, can produce behavioral changes with rapidity and reproducibility. Ethanol has little volume or distinguishing stereochemistry. Although it was once thought to interact nonspecifically with membrane lipids, a preponderance of evidence sugg...

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“…The ligand-gated potassium channels are members of a family of inward-rectifier potassium channels and are GIRK channels which are gated directly by GTP-binding protein βγ-subunit [11,28]. It was already reported that some psychotropic drugs with higher concentration ranges inhibited a cardiac type of GIRK channel in an over-expression system of Xenopus oocytes and CHO cells [16,17,28]. Moreover, it was reported that chlorpromazine inhibited the acetylcholine-induced I K.ACh with a threshold of ~30 nM in rat atrial cardiomyocyte [1].…”

Section: Discussionmentioning

confidence: 99%

“…Our group previously reported that benzodiazepines, antianxiety drugs, inhibited the acetylcholine receptor-operated potassium current (I K.ACh ) in relatively higher concentration than that of clinical concentration [26]. It was reported that a couple of antipsychotics and antidepressants inhibited GIRK channel current in an over-expression system [16,17]. Moreover, chlorpromazine inhibited I K.ACh in rat cardiac myocytes [1].…”

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confidence: 99%

Inhibitory Effects of Psychotropic Drugs on the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) in Guinea-Pig Atrial Myocytes

Okada

Watanabe

Matada

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (I K.ACh ) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. I K.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPγS). To elucidate mechanism for anticholinergic action, IC 50 ratio, the ratio of IC 50 for GTPγS-activated I K.ACh to CCh-induced I K.ACh , was calculated. Antipsychotics and antidepressants inhibited CCh-induced I K.ACh in a concentration-dependent manner. The IC 50 values were as follows; chlorpromazine 0.53 µM, clozapine 0.06 µM, fluphenazine 2.69 µM, haloperidol 2.66 µM, sulpiride 42.3 µM, thioridazine 0.07 µM, amitriptyline 0.03 µM, imipramine 0.22 µM and maprotiline 1.81 µM. The drugs, except for sulpiride, inhibited GTPγS-activated I K.ACh with following IC 50 values; chlorpromazine 1.71 µM, clozapine 14.9 µM, fluphenazine 3.55 µM, haloperidol 2.73 µM, thioridazine 1.90 µM, amitriptyline 7.55 µM, imipramine 7.09 µM and maprotiline 5.93 µM. The IC 50 ratio for fluphenazine and haloperidol was close to unity. The IC 50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress I K.ACh . Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel. KEY WORDS: acetylcholine receptor-operated potassium current, antidepressants, antipsychotics, atrial myocyte, patch clamp method.

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Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Cited by 82 publications

References 74 publications

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Ifenprodil

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Ifenprodil

Molecular mechanism underlying ethanol activation of G-protein–gated inwardly rectifying potassium channels

Inhibitory Effects of Psychotropic Drugs on the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) in Guinea-Pig Atrial Myocytes

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