K<sub>ir</sub>3.3 | Inwardly rectifying potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

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Target not currently curated in GtoImmuPdb

Target id: 436

Nomenclature: Kir3.3

Family: Inwardly rectifying potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 1 393 1q21-23 KCNJ9 potassium inwardly rectifying channel subfamily J member 9 20
Mouse 2 1 393 1 H3 Kcnj9 potassium inwardly-rectifying channel 13,19,29
Rat 2 1 393 13q24 Kcnj9 potassium inwardly-rectifying channel 6,28
Previous and Unofficial Names
potassium inwardly rectifying channel subfamily J member 9 | GIRK3 | G protein-activated inward rectifier potassium channel 3 | inward rectifier K(+) channel Kir3.3 | potassium channel, inwardly rectifying subfamily J, member 9 | potassium inwardly-rectifying channel | potassium voltage-gated channel subfamily J member 9
Database Links
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Kir3.1 11
Kir3.2 10
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
regulator of G-protein signaling 2 17
SNX27 21
Associated Protein Comments
Trafficking and expression:
  • Kir3.3 contains lysosomal targeting motif [23].
  • Kir3.3 contains PDZ binding motif that binds PDZ domain of SNX27 [3,21].
  • Evidence for formation of macromolecular signalling complexes containing Kir3.3 [4,7-8].
  • Surface expression of Kir3.2/Kir3.3 currents regulated by SNX27 in VTA DA neurons [25].
  • Regulation of Kir3.3-containing channels by SNX27 and Ras-like G proteins [2].
Functional Characteristics
G protein-activated inward-rectifier current
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  K+
References:  10-11
Ion Selectivity and Conductance Comments
Kir3.3 forms functional heteromers with Kir3.2 (31pS, [10]) and Kir3.1 (39pS, [11,14]).

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Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
PIP2 Hs - - - - - 9
Activator Comments
Kir3.3 in complex with Kir3.1 is activated by Gβγ subunits (pEC50 = 11 [11]).
Tissue Distribution
Pituitary, small intestine, testis, brain, fat, kidney, skeletal muscle, smooth muscle, pancreas.
Species:  Human
Technique:  RT-PCR
References:  28
Brain > skeletal muscle.
Species:  Mouse
Technique:  Northern Blot
References:  19
Brain (cortex, cerebellum, thalamus)
Species:  Mouse
Technique:  In situ hybridisation
References:  13
Cerebellum: Kir3.3 expression in Purkinje neurons (GIRK1/GIRK2/GIRK3), basket cells (GIRK1/GIRK3), stellate cells (GIRK3), and unipolar brush cells (GIRK2/GIRK3).
Species:  Mouse
References:  1
Brain (neocortex, olfactory system, hippocampus, thalamus > cerebellum, midbrain nuclei, brainstem nuclei, hypothalamus, amygdala, caudate putamen)
Species:  Rat
Technique:  In situ hybridisation
References:  6,12
Physiological Functions
Receptor-dependent hyperpolarisation of membrane potential.
Species:  None
Tissue:  Heterologous expression in Xenopus oocytes
References:  6,10-11
Activity dependent plasticity in GABAB-GIRK currents in ventral tegmental area dopaminergic neurons
Species:  Mouse
Tissue:  Ventral tegmental area
References:  18
Functional Kir3.2 and Kir3.3 heterotetramers in regulate neuronal excitability
Species:  Mouse
Tissue:  VTA and LC
References:  5,27
Decreased cocaine self-administration in mice lacking Kir3.3.
Species:  Mouse
References:  24
Contribution of Kir3.3 to GABAB receptor activated current
Species:  Mouse
Tissue:  Hippocampus
References:  15
Contribution of Kir3.3 to GABAB receptor currents in ventral tegmental area dopaminergic neurons affecting response to γ-hydroxybutyric acid
Species:  Mouse
Tissue:  Ventral tegmental area
References:  5,17
Channels containing Kir3.2 and Kir3.3 serve as an inhibitory gate in the locus coeruleus regulating morphine withdrawal
Species:  Mouse
Tissue:  Locus coeruleus
References:  15
Role for Kir3.3 in withdrawal from ethanol, pentobarbital and zolpidem
Species:  Mouse
References:  16
Kir3.3 knockout mice behave normally in open-field motor activity and habituation, anxiety-related behavior, motor co-ordination and ataxia and operant performance
Species:  Mouse
References:  26
Physiological Functions Comments
For review see [22].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnj9tm1Kwn Kcnj9tm1Kwn/Kcnj9tm1Kwn
involves: 129X1/SvJ
MGI:108007  MP:0003635 abnormal synaptic transmission PMID: 12040038 
Kcnj6tm1Stf|Kcnj9tm1Kwn Kcnj6tm1Stf/Kcnj6tm1Stf,Kcnj9tm1Kwn/Kcnj9tm1Kwn
involves: 129S1/Sv * 129X1/SvJ
MGI:104781  MGI:108007  MP:0003635 abnormal synaptic transmission PMID: 12040038 
Kcnj6tm1Stf|Kcnj9tm1Kwn Kcnj6tm1Stf/Kcnj6tm1Stf,Kcnj9tm1Kwn/Kcnj9tm1Kwn
involves: 129S1/Sv * 129X1/SvJ
MGI:104781  MGI:108007  MP:0002083 premature death PMID: 12040038 
Kcnj6tm1Stf|Kcnj9tm1Kwn Kcnj6tm1Stf/Kcnj6tm1Stf,Kcnj9tm1Kwn/Kcnj9tm1Kwn
involves: 129S1/Sv * 129X1/SvJ
MGI:104781  MGI:108007  MP:0002064 seizures PMID: 12040038 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
References:  28


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1. Aguado C, Colón J, Ciruela F, Schlaudraff F, Cabañero MJ, Perry C, Watanabe M, Liss B, Wickman K, Luján R. (2008) Cell type-specific subunit composition of G protein-gated potassium channels in the cerebellum. J. Neurochem., 105 (2): 497-511. [PMID:18088366]

2. Balana B, Bahima L, Bodhinathan K, Taura JJ, Taylor NM, Nettleton MY, Ciruela F, Slesinger PA. (2013) Ras-association domain of sorting Nexin 27 is critical for regulating expression of GIRK potassium channels. PLoS ONE, 8 (3): e59800. [PMID:23536889]

3. Balana B, Maslennikov I, Kwiatkowski W, Stern KM, Bahima L, Choe S, Slesinger PA. (2011) Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27. Proc. Natl. Acad. Sci. U.S.A., 108 (14): 5831-6. [PMID:21422294]

4. Ciruela F, Fernández-Dueñas V, Sahlholm K, Fernández-Alacid L, Nicolau JC, Watanabe M, Luján R. (2010) Evidence for oligomerization between GABAB receptors and GIRK channels containing the GIRK1 and GIRK3 subunits. Eur. J. Neurosci., 32 (8): 1265-77. [PMID:20846323]

5. Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, Lüscher C. (2004) Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat. Neurosci., 7 (2): 153-9. [PMID:14745451]

6. Dissmann E, Wischmeyer E, Spauschus A, Pfeil DV, Karschin C, Karschin A. (1996) Functional expression and cellular mRNA localization of a G protein-activated K+ inward rectifier isolated from rat brain. Biochem. Biophys. Res. Commun., 223 (2): 474-9. [PMID:8670306]

7. Fernández-Alacid L, Aguado C, Ciruela F, Martín R, Colón J, Cabañero MJ, Gassmann M, Watanabe M, Shigemoto R, Wickman K et al.. (2009) Subcellular compartment-specific molecular diversity of pre- and post-synaptic GABA-activated GIRK channels in Purkinje cells. J. Neurochem., 110 (4): 1363-76. [PMID:19558451]

8. Fowler CE, Aryal P, Suen KF, Slesinger PA. (2007) Evidence for association of GABA(B) receptors with Kir3 channels and regulators of G protein signalling (RGS4) proteins. J. Physiol. (Lond.), 580 (Pt 1): 51-65. [PMID:17185339]

9. Hilgemann DW, Ball R. (1996) Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. Science, 273 (5277): 956-9. [PMID:8688080]

10. Jelacic TM, Kennedy ME, Wickman K, Clapham DE. (2000) Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. J. Biol. Chem., 275 (46): 36211-6. [PMID:10956667]

11. Jelacic TM, Sims SM, Clapham DE. (1999) Functional expression and characterization of G-protein-gated inwardly rectifying K+ channels containing GIRK3. J. Membr. Biol., 169 (2): 123-9. [PMID:10341034]

12. Karschin C, Karschin A. (1997) Ontogeny of gene expression of Kir channel subunits in the rat. Mol. Cell. Neurosci., 10 (3-4): 131-48. [PMID:9532576]

13. Kobayashi T, Ikeda K, Ichikawa T, Abe S, Togashi S, Kumanishi T. (1995) 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. Biochem. Biophys. Res. Commun., 208 (3): 1166-73. [PMID:7702616]

14. Kofuji P, Davidson N, Lester HA. (1995) Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by G beta gamma subunits and function as heteromultimers. Proc. Natl. Acad. Sci. U.S.A., 92 (14): 6542-6. [PMID:7604029]

15. Koyrakh L, Luján R, Colón J, Karschin C, Kurachi Y, Karschin A, Wickman K. (2005) Molecular and cellular diversity of neuronal G-protein-gated potassium channels. J. Neurosci., 25 (49): 11468-78. [PMID:16339040]

16. Kozell LB, Walter NA, Milner LC, Wickman K, Buck KJ. (2009) Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identify a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem, and ethanol. J. Neurosci., 29 (37): 11662-73. [PMID:19759313]

17. Labouèbe G, Lomazzi M, Cruz HG, Creton C, Luján R, Li M, Yanagawa Y, Obata K, Watanabe M, Wickman K et al.. (2007) RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nat. Neurosci., 10 (12): 1559-68. [PMID:17965710]

18. Lalive AL, Munoz MB, Bellone C, Slesinger PA, Lüscher C, Tan KR. (2014) Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity. J. Neurosci., 34 (15): 5107-14. [PMID:24719090]

19. Lesage F, Duprat F, Fink M, Guillemare E, Coppola T, Lazdunski M, Hugnot JP. (1994) Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett., 353 (1): 37-42. [PMID:7926018]

20. Lesage F, Fink M, Barhanin J, Lazdunski M, Mattéi MG. (1995) Assignment of human G-protein-coupled inward rectifier K+ channel homolog GIRK3 gene to chromosome 1q21-q23. Genomics, 29 (3): 808-9. [PMID:8575783]

21. Lunn ML, Nassirpour R, Arrabit C, Tan J, McLeod I, Arias CM, Sawchenko PE, Yates 3rd JR, Slesinger PA. (2007) A unique sorting nexin regulates trafficking of potassium channels via a PDZ domain interaction. Nat. Neurosci., 10 (10): 1249-59. [PMID:17828261]

22. Lüscher C, Slesinger PA. (2010) Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat. Rev. Neurosci., 11 (5): 301-15. [PMID:20389305]

23. Ma D, Zerangue N, Raab-Graham K, Fried SR, Jan YN, Jan LY. (2002) Diverse trafficking patterns due to multiple traffic motifs in G protein-activated inwardly rectifying potassium channels from brain and heart. Neuron, 33 (5): 715-29. [PMID:11879649]

24. Morgan AD, Carroll ME, Loth AK, Stoffel M, Wickman K. (2003) Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice. Neuropsychopharmacology, 28 (5): 932-8. [PMID:12637950]

25. Munoz MB, Slesinger PA. (2014) Sorting nexin 27 regulation of G protein-gated inwardly rectifying K⁺ channels attenuates in vivo cocaine response. Neuron, 82 (3): 659-69. [PMID:24811384]

26. Pravetoni M, Wickman K. (2008) Behavioral characterization of mice lacking GIRK/Kir3 channel subunits. Genes Brain Behav., 7 (5): 523-31. [PMID:18194467]

27. Torrecilla M, Marker CL, Cintora SC, Stoffel M, Williams JT, 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 (11): 4328-34. [PMID:12040038]

28. Vaughn J, Wolford JK, Prochazka M, Permana PA. (2000) Genomic structure and expression of human KCNJ9 (Kir3.3/GIRK3). Biochem. Biophys. Res. Commun., 274 (2): 302-9. [PMID:10913335]

29. Wickman K, Pu WT, Clapham DE. (2002) Structural characterization of the mouse Girk genes. Gene, 284 (1-2): 241-50. [PMID:11891065]


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