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

Top ▲


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 voltage-gated channel subfamily J member 9 20
Mouse 2 1 393 1 H3 Kcnj9 potassium inwardly-rectifying channel, subfamily J, member 9 13,19,29
Rat 2 1 393 13q24 Kcnj9 potassium voltage-gated channel subfamily J member 9 6,28
Previous and Unofficial Names
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
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]).

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
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
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
Activity dependent plasticity in GABAB-GIRK currents in ventral tegmental area dopaminergic neurons
Species:  Mouse
Tissue:  Ventral tegmental area
References:  18
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

Show »

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


Show »

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]


Show »

How to cite this page

John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Colin G. Nichols, Lawrence G. Palmer, Wade L. Pearson, Henry Sackin, Susumu Seino, Paul A. Slesinger, Stephen Tucker, Carol A. Vandenberg.
Inwardly rectifying potassium channels: Kir3.3. Last modified on 27/02/2018. Accessed on 19/07/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=436.