TABLE 7

Kir3.2 channels

Channel name Kir3.2
Description G-protein gated, inwardly rectifying potassium channel Kir3.2 subunit
Other names GIRK2, hiGIRK2
Molecular information Human (KCNJ6): 423aa, Locus ID: 3763, GenBank: U24660, U52153, NM_002240, PMID: 7592809,1 10659995,2 chr. 21q22.13-q22.2
Rat (Kcnj6): 414aa, Locus ID: 25743, GenBank: AB073753, NM_013192, PMID: 11883954,3 chr. 11q21
Mouse (Kcnj6): 414aa, Locus ID: 16522, GenBank: U37253, NM_010606, PMID: 7499385,4 chr. 16, 68.75 centimorgans
Associated subunits Kir3.1, Kir3.3, and Kir3.4 to form heteromeric channels; no auxiliary subunit is reported
Functional assays Voltage-clamp
Current IGIRK
Conductance 30pS for Kir3.2c homomeric channel in 150 mM symmetric K+,5 32pS for Kir3.2d in 140 mM symmetric K+,6 35–37pS for Kir3.2/Kir3.1 heteromeric channel in 150 mM symmetric K+,5 31pS for Kir3.2/Kir3.3 in 140 mM symmetric K+7
Ion selectivity K+8
Activation G protein βγ subunits EC50: 53 nM for Kir3.2/Kir3.37
Inactivation Voltage- and RGS protein-dependent9,10
Activators G protein βγ subunits (EC50, not established), PIP2 (EC50, not established11), sodium (EC50 to Kir3.2c homomeric channel, 37 mM; EC50 to Kir3.2c/Kir3.1, 27 mM12), ethanol (Kir3.2-containing Kir channel is reported to be sensitive to ethanol compared with the others (100 mM ethanol increases the basal current amplitude of either Kir3.2 or Kir3.2/Kir3.1 by about 40%13,14)
Gating inhibitors G protein α subunits by binding G protein βγ subunits15
Blockers Ba2+ (not established), Cs+ (not established), tertiapin (IC50 to Kir3.2d, 7 nM; to Kir3.1/Kir3.2d, 5.4 nM16), halothane (IC50 to Kir3.2, 60 μM17), 1-chloro-1,2,2-trifluorocyclobutane (IC50 not assigned by the authors18), bupivacaine (Ki to Kir3.2, 500 μM; Ki to Kir3.1/Kir3.2, 107 μM19), antipsychotic drug (IC50 to Kir3.1/Kir3.2 for haloperidol, 75.5 μM; for thioridazine, 57.6 μM; for pimozide, 2.96 μM; for clozapine, 179 μM20), fluoxetine (Prozac) (IC50 to Kir3.2, 89.5 μM; to Kir3.1/Kir3.2, 16.9 μM21), SCH23390; IC50 to Kir3.1/Kir3.2, 7.8 μM; to Kir3.2, 83 μM22), Verapamil (IC50 to Kir3.1/Kir3.2, 120 μM23), MK-801 (IC50 to Kir3.1/Kir3.2, 200 μM23), QX-314 (IC50 to Kir3.1/Kir3.2, 200 μM23)
Radioligands None
Channel distribution Distribution of Kir3.2 is related to the expression of the isoforms; at least seven exons contribute to produce alternative splicing variants6,24, 25; at least four splice variants are known (numbers in parentheses are GenBank accession numbers and PMID accession numbers, respectively); Kir3.2a (rat: AB07375,4 118839543; mouse: U11859, 79260184) is specifically expressed in brain26 and exists as a channel in heterologous complex with either Kir3.1 (throughout the brain27) or Kir3.2c (dopaminergic neurons in substantia nigra28); Kir3.2b (rat: AB07375,6 118839543; mouse: D86040, 857314729) is ubiquitously expressed; Kir3.2c (human: U24660, 7592809,1 rat: AB07375,3 118839543; mouse: U37253, 749938530) is expressed in the brain and exists as a heterologous channel in the complex with either Kir3.1 (throughout the brain27) or Kir3.2a (dopaminergic neurons in substantia nigra28); in pancreatic α-cells, Kir3.2c coexpresses with Kir3.431; Kir3.2d (mouse; AB02950,2 105623316) shows specific expression in testis and behaves as a homomeric channel6; in the brain, some parts of Kir3.2 isoforms exist as a complex not only with Kir3.1 but also with Kir3.37,32 and Kir3.430
Physiological functions Kir3.2 participates in the formation of the slow inhibitory postsynaptic potential28,33 and probably in the presynaptic inhibition in the brain; in the endocrine organs, neurotransmitters induce hyperpolarization of the membrane potential and lead to the inhibition of hormone secretion31,34; Kir3.2d possibly involves in spermatogenesis6
Mutations and pathophysiology Weaver (WV) mouse has been isolated to have a natural mutation at a glycine to serine at residue 15635; the mutant channel permits ion flow for both potassium and sodium ions8 and reduces the sensitivity to G protein βγ subunit36; Kir3.2-null mice show the spontaneous tonic-clonic seizures33; an immunocytochemical study suggested that expression of the mutated channel is not a sufficient condition to induce cell death in the ventral mesencephalon of the wv/wv mice37
Pharmacological significance Not established

  • aa, amino acids; chr., chromosome; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; MK-801, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; QX-314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium.

  • ↵1. Ferrer J, Nichols CG, Makhina EN, Salkoff L, Bernstein J, Gerhard D, Wasson J, Ramanadham S, and Permutt A (1995) Pancreatic islet cells express a family of inwardly rectifying K+ channel subunits which interact to form G-protein-activated channels. J Biol Chem 270:26086-26091

  • ↵2. Schoots O, Wilson JM, Ethier N, Bigras E, Hebert T, and Val Tol HH (1999) Co-expression of human Kir3 subunits can yield channels with different functional properties. Cell Signal 11:871-883

  • ↵3. Suda S, Nibuya M, Suda H, Takamatsu K, Miyazaki T, Nomura S, and Kawai N (2002) Potassium channel mRNAs with AU-rich elements and brain specific expression. Biochem Biophys Res Commun 291:1265-1271

  • ↵4. Lesage F, Duprat F, Fink M, Guillemare E, Coppola T, Lazdunski M, and Hugnot JP (1994) Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett 353:37-42

  • ↵5. Kofuji P, Davidson N, and Lester HA (1995) Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by Gβγ subunits and function as heteromultimers. Proc Natl Acad Sci USA 92:6542-6546

  • ↵6. Inanobe A, Horio Y, Fujita A, Tanemoto M, Hibino H, Inageda K, and Kurachi Y (1999) Molecular cloning and characterization of a novel splicing variant of the Kir3.2 subunit predominantly expressed in mouse testis. J Physiol 521:19-30

  • ↵7. Jelacic TM, Kennedy ME, Wickman K, and Clapham DE (2000) Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ channels composed of GIRK2 and GIRK3. J Biol Chem 275:36211-36216

  • ↵8. Slesinger PA, Patil N, Liao YJ, Jan YN, Jan LY, and Cox DR (1996) Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels. Neuron 16:321-331

  • ↵9. Doupnik CA, Davidson N, Lester HA, and Kofuji P (1997) RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K+ channels. Proc Natl Acad Sci USA 94:10461-10466

  • ↵10. Saitoh O, Kubo Y, Miyatani Y, Asano T, and Nakata H (1997) RGS8 accelerates G-protein-mediated modulation of K+ currents. Nature (Lond) 390:525-529

  • ↵11. Huang C-L, Feng S, and Hilgemann DW (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature (Lond) 391:803-806

  • ↵12. Ho IH and Murrell-Lagnado RD (1999) Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. J Biol Chem 274:8639-8648

  • ↵13. Lewohl JM, Wilson WR, Mayfield RD, Brozowski SJ, Morrisett RA, and Harris RA (1999) G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci 2:1084-1090

  • ↵14. Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, and Kumanishi T (1999) Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci 2:1091-1097

  • ↵15. Peleg S, Varon D, Ivanina T, Dessauer CW, and Dascal N (2002) Gαi controls the gating of the G protein-activated K+ channel GIRK. Neuron 33:87-99

  • ↵16. Matsushita K, Fujita A, Makino Y, Fujita S, Tanemoto M, and Kurachi Y (2000) Effect of bee toxin tertiapin on cloned inwardly rectifying potassium channels. Jpn J Pharmacol 82(Suppl. 1):130P

  • ↵17. Weigl LG and Schreibmayer W (2001) G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics. Mol Pharmacol 60:282-289

  • ↵18. Yamakura T, Lewohl JM, and Harris RA (2001) Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels. Anesthesiology 95:144-153

  • ↵19. Zhou W, Arrabit C, Choe S, and Slesinger PA (2001) Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels. Proc Natl Acad Sci USA 98:6482-6487

  • ↵20. Kobayashi T, Ikeda K, and Kumanishi T (2000) Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K+ (GIRK) channels expressed in Xenopus oocytes. Br J Pharmacol 129:1716-1722

  • ↵21. Kobayashi T, Washiyama K, and Ikeda K (2003) Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac). Br J Pharmacol 138:1119-1128

  • ↵22. Kuzhikandathil EV and Oxford GS (2002) Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels. Mol Pharmacol 62:119-126

  • ↵23. Kofuji P, Hofer M, Millen KJ, Millonig JH, Davidson N, Lester HA, and Hatten ME (1996) Functional analysis of the weaver mutant GIRK2 K+ channel and rescue of weaver granule cells. Neuron 16:941-952

  • ↵24. Wei J, Hodes ME, Piva R, Feng Y, Wang Y, Ghetti B, and Dlouhy SR (1998) Characterization of murine Girk2 transcript isoforms: structure and differential expression. Genomics 51:379-390

  • ↵25. Wickman K, Pu WT, and Clapham DE (2002) Structural characterization of the mouse Girk genes. Gene 284:241-250

  • ↵26. Murer G, Adelbrecht C, Lauritzen I, Lesage F, Lazdunski M, Agid Y, and Raisman-Vozari R (1997) An immunocytochemical study on the distribution of two G-protein-gated inward rectifier potassium channels (GIRK2 and GIRK4) in the adult rat brain. Neuroscience 80:345-357

  • ↵27. Liao YJ, Jan YN, and Jan LY (1996) Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. J Neurosci 16:7137-7150

  • ↵28. Inanobe A, Yoshimoto Y, Horio Y, Morishige K, Hibino H, Matsumoto S, Tokunaga Y, Maeda T, Hata Y, Takai Y, et al. (1999) Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra. J Neurosci 19:1006-1017

  • ↵29. Isomoto S, Kondo C, Takahashi N, Matsumoto S, Yamada M, Takumi T, Horio Y, and Kurachi Y (1996) A novel ubiquitously distributed isoform of GIRK2 (GIRK2B) enhances GIRK1 expression of the G-protein-gated K+ current in Xenopus oocytes. Biochem Biophys Res Commun 218:286-291

  • ↵30. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, Romey G, Barhanin J, and Lazdunski M (1995) Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem 270:28660-28667

  • ↵31. Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M, and Kurachi Y (1999) Somatostatin induces hyperpolarization in pancreatic islet α cells by activating a G protein-gated K+ channel. FEBS Lett 444:265-269

  • ↵32. Torrecilla M, Marker CL, Cintora SC, Stoffel M, Williams JT, and Wickman K (2002) G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J Neurosci 22:4328-4334

  • ↵33. Signorini S, Liao YJ, Duncan SA, Jan LY, and Stoffel M (1997) Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled inwardly rectifying K+ channel GIRK2. Proc Natl Acad Sci USA 94:923-927

  • ↵34. Morishige K, Inanobe A, Yoshimoto Y, Kurachi H, Murata Y, Tokunaga Y, Maeda T, Maruyama Y, and Kurachi Y (1999) Secretagogue-induced exocytosis recruits G protein-gated K+ channels to plasma membrane in endocrine cells. J Biol Chem 274:7969-7974

  • ↵35. Patil N, Cox DR, Bhar D, Faham M, Myers RM, and Peterson AS (1995) A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nat Genet 11:126-129

  • ↵36. Navarro B, Kennedy ME, Velimirović B, Bhat D, Peterson AS, and Clapham DE (1996) Nonselective and Gβγ-insensitive weaver K+ channels. Science 272:1950-1953

  • ↵37. Adelbrecht C, Murer MG, Lauritzen I, Lesage F, Ladzunski M, Agid Y, and Raisman-Vozari R (1997) An immunocytochemical study of a G-protein-gated inward rectifier K+ channel (GIRK2) in the weaver mouse mesencephalon. NeuroReport 8:969-974