Nishizawa D et al. (2011), Identification of selective agonists and antago...

XB-ART-43817

Curr Neuropharmacol 2011 Mar 01;91:113-7. doi: 10.2174/157015911795017227.

Show Gene links Show Anatomy links

Identification of selective agonists and antagonists to g protein-activated inwardly rectifying potassium channels: candidate medicines for drug dependence and pain.

Nishizawa D , Gajya N , Ikeda K .

???displayArticle.abstract???
G protein-activated inwardly rectifying K(+) (GIRK) channels have been known to play a key role in the rewarding and analgesic effects of opioids. To identify potent agonists and antagonists to GIRK channels, we examined various compounds for their ability to activate or inhibit GIRK channels. A total of 503 possible compounds with low molecular weight were selected from a list of fluoxetine derivatives at Pfizer Japan Inc. We screened these compounds by a Xenopus oocyte expression system. GIRK1/2 and GIRK1/4 heteromeric channels were expressed on Xenopus laevis oocytes at Stage V or VI. A mouse IRK2 channel, which is another member of inwardly rectifying potassium channels with similarity to GIRK channels, was expressed on the oocytes to examine the selectivity of the identified compounds to GIRK channels. For electrophysiological analyses, a two-electrode voltage clamp method was used. Among the 503 compounds tested, one compound and three compounds were identified as the most effective agonist and antagonists, respectively. All of these compounds induced only negligible current responses in the oocytes expressing the IRK2 channel, suggesting that these compounds were selective to GIRK channels. These effective and GIRK-selective compounds may be useful possible therapeutics for drug dependence and pain.

???displayArticle.pubmedLink??? 21886574
???displayArticle.pmcLink??? PMC3137163
???displayArticle.link??? Curr Neuropharmacol

Species referenced: Xenopus laevis
Genes referenced: kcnj12 kcnj3

???attribute.lit??? ???displayArticles.show???

References [+] :

Blednov, A pervasive mechanism for analgesia: activation of GIRK2 channels. 2003, Pubmed

Blednov, A pervasive mechanism for analgesia: activation of GIRK2 channels. 2003, Pubmed
Corey, Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers. 1998, Pubmed
Ikeda, Opioid receptor coupling to GIRK channels. In vitro studies using a Xenopus oocyte expression system and in vivo studies on weaver mutant mice. 2003, Pubmed , Xenbase
Ikeda, Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? 2002, Pubmed
Jelacic, Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. 2000, Pubmed
Kobayashi, Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac). 2003, Pubmed , Xenbase
Kobayashi, Molecular cloning of a mouse G-protein-activated K+ channel (mGIRK1) and distinct distributions of three GIRK (GIRK1, 2 and 3) mRNAs in mouse brain. 1995, Pubmed
Kobayashi, Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine. 2006, Pubmed , Xenbase
Kobayashi, Effects of clozapine on the delta- and kappa-opioid receptors and the G-protein-activated K+ (GIRK) channel expressed in Xenopus oocytes. 1998, Pubmed , Xenbase
Kobayashi, Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes. 2000, Pubmed , Xenbase
Kobayashi, Modulators of G protein-activated inwardly rectifying K+ channels: potentially therapeutic agents for addictive drug users. 2004, Pubmed , Xenbase
Kobayashi, Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. 2004, Pubmed , Xenbase
Kobayashi, Ethanol opens G-protein-activated inwardly rectifying K+ channels. 1999, Pubmed , Xenbase
Lewohl, G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. 1999, Pubmed , Xenbase
Marker, Hyperalgesia and blunted morphine analgesia in G protein-gated potassium channel subunit knockout mice. 2002, Pubmed
Marker, Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. 2004, Pubmed
Marker, Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. 2005, Pubmed
Mitrovic, Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. 2003, Pubmed
Morgan, Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice. 2003, Pubmed
Weigl, G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics. 2001, Pubmed , Xenbase
Wickman, Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. 2000, Pubmed
Wickman, Abnormal heart rate regulation in GIRK4 knockout mice. 1998, Pubmed

	Fig. (1). Current Responses Induced by the Selected PF Compound Pools in the First Screening Step. Normalized current responses to the pools of PF compounds by the response to BaCl2. PF 9 – PF 12, PF 401 – PF 404, and PF 409 – PF 412 pools were selected as candidate agonists, and PF 37 – PF 40, PF 157 – PF 160, PF 185 – PF 188, PF 233 – PF 236, and PF 245 – PF 248 pools were selected as candidate antagonists. The PF 417 – PF 420 pool was selected as a candidate agonist or antagonist in the first screening step.
	Fig. (2). Candidate Agonist and Antagonists Identified in the Second Screening Step. PF 419 was selected as a candidate agonist, and PF 40, PF 236, and PF 246 were selected as candidate antagonists in the second screening step. a. Traces of typical current responses to PF 419 (30 µM) and BaCl2 (2 mM) in the oocyte expressing the GIRK1/4 channel. The striped and filled bars represent the duration of the application of PF 419 and BaCl2, respectively. b. The normalized current responses to the selected PF compounds by the response to BaCl2.
	Fig. (3). Concentration-Response Relationships of the Identified Agonist and Antagonists to GIRK Channels. a. Current response was normalized by the response to ethanol (100 mM). b-d. Current responses were normalized by the response to BaCl2 (2 mM). P < 0.005 between GIRK1/2 and GIRK1/4. *P < 0.001 between GIRK1/2 and GIRK1/4.