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Kir3.1

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Target id: 434

Nomenclature: Kir3.1

Family: Inwardly rectifying potassium channels (KIR)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 1 501 2q24.1 KCNJ3 potassium inwardly rectifying channel subfamily J member 3 44
Mouse 2 1 501 2 C1.1 Kcnj3 potassium inwardly-rectifying channel, subfamily J, member 3 21,47
Rat 2 1 501 3q21 Kcnj3 potassium inwardly-rectifying channel, subfamily J, member 3 5,26
Previous and Unofficial Names Click here for help
potassium inwardly rectifying channel subfamily J member 3 | GIRK1 | G protein-activated inward rectifier potassium channel 1 | Kcnf3 | potassium channel, inwardly rectifying subfamily J, member 3 | potassium channel subunit Kir3.1 type 3 delta | potassium inwardly-rectifying channel | potassium voltage-gated channel subfamily J member 3
Database Links Click here for help
Alphafold P48549 (Hs), P63250 (Mm), P63251 (Rn)
CATH/Gene3D 2.60.40.1400
ChEMBL Target CHEMBL1914277 (Hs), CHEMBL3832643 (Rn)
Ensembl Gene ENSG00000162989 (Hs), ENSMUSG00000026824 (Mm), ENSRNOG00000005369 (Rn)
Entrez Gene 3760 (Hs), 16519 (Mm), 50599 (Rn)
Human Protein Atlas ENSG00000162989 (Hs)
KEGG Gene hsa:3760 (Hs), mmu:16519 (Mm), rno:50599 (Rn)
OMIM 601534 (Hs)
Pharos P48549 (Hs)
RefSeq Nucleotide NM_002239 (Hs), NM_008426 (Mm), NM_031610 (Rn)
RefSeq Protein NP_002230 (Hs), NP_032452 (Mm), NP_113798 (Rn)
UniProtKB P48549 (Hs), P63250 (Mm), P63251 (Rn)
Wikipedia KCNJ3 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structural Basis of Inward Rectification: Cytoplasmic Pore of the G Protein-Gated Inward Rectifier Kir3.1 at 1.8 A Resolution
PDB Id:  1N9P
Resolution:  1.8Å
Species:  Mouse
References:  37
Image of receptor 3D structure from RCSB PDB
Description:  Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification
PDB Id:  1U4E
Resolution:  2.09Å
Species:  Mouse
References:  39
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of a Kir3.1-prokaryotic Kir channel chimera
PDB Id:  2QKS
Resolution:  2.2Å
Species:  Mouse
References:  36
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Kir3.4 25
Kir3.3 15
Kir3.2 23,29
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Gβγ 14,27,31,42,48
regulator of G-protein signaling 8 6,43
regulator of G-protein signaling 1 6,9
regulator of G-protein signaling 3 6,9
regulator of G-protein signaling 4 6,9
Associated Protein Comments
Kir3.1 is not functional alone. The functional expression of Kir3.1 in Xenopus oocytes requires coassembly with the endogenous Xenopus Kir3.5 subunit [11]. The major functional assembly in the heart is the Kir3.1/3.4 heteromultimer [25], while in the brain it is Kir3.1/3.2, Kir3.1/3.3 and Kir3.2/3.3 [1,3-4,7,23-24,28-29,33,46].
Functional Characteristics Click here for help
G protein-activated inward-rectifier current
Ion Selectivity and Conductance Click here for help
Species:  Rat
Rank order:  K+ [42.0 pS]
References:  26
Ion Selectivity and Conductance Comments
Please see [27,34] for review.

Kir3.1 forms functional heteromers with Kir3.3 (39pS, [15]) and Kir3.4 (K+, 36.6pS [25]).

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
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
ethanol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Agonist - - 1x10-2 Physiological 22,30
⤷ Conc range: 1x10-2 M [22,30]
Holding voltage: Physiological
PIP2 Small molecule or natural product Ligand is endogenous in the given species ? Agonist 6.3 pKd 5x10-5 Physiological 13
⤷ pKd 6.3 (Kd 5.01x10-7 M) Conc range: 5x10-5 M [13]
Holding voltage: Physiological
ML297 Small molecule or natural product Hs - 6.7 pEC50 1x10-5 Physiological 20
⤷ pEC50 6.7 (EC50 1.9x10-7 M) Conc range: 1x10-5 M [20]
Holding voltage: Physiological
VU0810464 Small molecule or natural product Hs Activation 6.1 – 6.8 pEC50 - - 49
⤷ pEC50 6.8 (EC50 1.65x10-7 M) [49]
Description: Activation of Kir pEC50 6.1 (EC50 7.2x10-7 M) [49]
Description: Activation of Kir3.1/3.4 (cardiac type) multimeric channels expressed in HEK-293 cells.
Na+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 1.4 – 1.6 pEC50 - -80.0 12
⤷ pEC50 1.4 – 1.6 [12]
Holding voltage: -80.0 mV
View species-specific activator tables
Activator Comments
Kir3.1 is also activated by Gβγ [13-14,27,42,48] and modulated by RGS8 [43] and RGS2 [6].
Gating Inhibitor Comments
Gα subunits inhibit the receptor by reducing the availability of Gβγ subunits for activation [45]. Gα subunits bind to Kir3.1 [40]. ER retention motif identified in K3.1 [35]. SNX27 regulates trafficking of Kir3.1 and Kir3.3 channels [32].
Channel Blockers
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
Ba2+ Click here for species-specific activity table Hs Antagonist - - 1x10-4 - 3x10-4 Physiological 44
⤷ Conc range: 1x10-4 - 3x10-4 M [44]
Holding voltage: Physiological
Ba2+ Click here for species-specific activity table Rn Antagonist - - 1x10-4 - 2.5x10-4 Physiological 5
⤷ Conc range: 1x10-4 - 2.5x10-4 M [5]
Holding voltage: Physiological
tertiapin-Q Peptide Click here for species-specific activity table Rn Antagonist 8.0 pEC50 - Physiological 17
⤷ pEC50 8.0 (EC50 1x10-8 M) [17]
Holding voltage: Physiological
tertiapin-Q Peptide N/A Antagonist 7.9 pIC50 - - 16
⤷ pIC50 7.9 Kir3.1/3.4; expression in Xenopus oocytes [16]
AZD2927 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs - 5.9 pIC50 - - 2
⤷ pIC50 5.9 (IC50 1.3x10-6 M) [2]
Ba2+ Click here for species-specific activity table Rn Antagonist 4.7 pIC50 - - 5
⤷ pIC50 4.7 Kir3.1 expressed in Xenopus oocytes [5]
View species-specific channel blocker tables
Channel Blocker Comments
These studies were performed using Kir3.1 expressed in Xenopus oocytes.
Tissue Distribution Click here for help
Cerebellum-Kir3.3 expression in Purkinje neurons (Kir3.1/Kir3.2/Kir3.3), basket cells (Kir3.1/Kir3.2), stellate cells (Kir3.3), and unipolar brush cells (Kir3.2/Kir3.3).
Species:  Mouse
Technique: 
References:  1
Forebrain, cerebellum, atrium.
Species:  Rat
Technique:  Northern Blot
References:  26
Olfactory bulb (piriform cortex), neocortex (layers 2-6), hippocampus (dentate gyrus granule cells), basal ganglia (habenula), thalamus midbrain (inferior colliculus), cerebellum (granule cell layer), brainstem (pontine nucleus).
Species:  Rat
Technique:  In situ hybridisation
References:  18
Developmental expression of Kir3.1 in brain.
Species:  Rat
Technique:  In situ hybridisation
References:  19
Physiological Functions Comments
  • Kir3.1 is known to be associated with slow receptor-dependent hyperpolarisation of membrane potential in hippocampus [33].
  • Muscarinic receptor dependent desensitization of IKACh depends on hydrolysis of PIP2 [22].
  • Repeated cocaine weakens GABAB-Kir3 currents in prelimbic mouse cortex [10].
  • RGS4 associates with GABAB receptors and Kir3.1/3.4 channels [8].
  • Single injection of methamphetamine reduces GABAB-Kir3 currents in VTA GABA neurons [38].
  • Modest behavioural deficits in Kir3.1 knockout mice [41].
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnj3tm1Kwn Kcnj3tm1Kwn/Kcnj3tm1Kwn
involves: 129X1/SvJ		 MGI:104742  MP:0004215 abnormal myocardial fiber physiology PMID: 12374786 
Kcnj3tm1Kwn Kcnj3tm1Kwn/Kcnj3tm1Kwn
involves: 129X1/SvJ		 MGI:104742  MP:0002626 increased heart rate PMID: 12374786 

References

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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. AstraZeneca. AZD2927. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd2927/

3. 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]

4. 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]

5. Dascal N, Schreibmayer W, Lim NF, Wang W, Chavkin C, DiMagno L, Labarca C, Kieffer BL, Gaveriaux-Ruff C, Trollinger D et al.. (1993) Atrial G protein-activated K+ channel: expression cloning and molecular properties. Proc Natl Acad Sci USA, 90 (21): 10235-9. [PMID:8234283]

6. Doupnik CA, Davidson N, Lester HA, Kofuji P. (1997) RGS proteins reconstitute the rapid gating kinetics of gbetagamma-activated inwardly rectifying K+ channels. Proc Natl Acad Sci USA, 94 (19): 10461-6. [PMID:9294233]

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. Fujita S, Inanobe A, Chachin M, Aizawa Y, Kurachi Y. (2000) A regulator of G protein signalling (RGS) protein confers agonist-dependent relaxation gating to a G protein-gated K+ channel. J Physiol (Lond.), 526 Pt 2: 341-7. [PMID:10896722]

10. Hearing M, Kotecki L, Marron Fernandez de Velasco E, Fajardo-Serrano A, Chung HJ, Luján R, Wickman K. (2013) Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron, 80 (1): 159-70. [PMID:24094109]

11. Hedin KE, Lim NF, Clapham DE. (1996) Cloning of a Xenopus laevis inwardly rectifying K+ channel subunit that permits GIRK1 expression of IKACh currents in oocytes. Neuron, 16 (2): 423-9. [PMID:8789957]

12. Ho IH, Murrell-Lagnado RD. (1999) Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. J Biol Chem, 274 (13): 8639-48. [PMID:10085101]

13. Huang CL, Feng S, Hilgemann DW. (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature, 391 (6669): 803-6. [PMID:9486652]

14. Huang CL, Slesinger PA, Casey PJ, Jan YN, Jan LY. (1995) Evidence that direct binding of G beta gamma to the GIRK1 G protein-gated inwardly rectifying K+ channel is important for channel activation. Neuron, 15 (5): 1133-43. [PMID:7576656]

15. 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]

16. Jin W, Klem AM, Lewis JH, Lu Z. (1999) Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q. Biochemistry, 38 (43): 14294-301. [PMID:10572004]

17. Jin W, Lu Z. (1998) A novel high-affinity inhibitor for inward-rectifier K+ channels. Biochemistry, 37 (38): 13291-9. [PMID:9748337]

18. Karschin C, Dissmann E, Stühmer W, Karschin A. (1996) IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J Neurosci, 16 (11): 3559-70. [PMID:8642402]

19. 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]

20. Kaufmann K, Romaine I, Days E, Pascual C, Malik A, Yang L, Zou B, Du Y, Sliwoski G, Morrison RD et al.. (2013) ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chem Neurosci, 4 (9): 1278-86. [PMID:23730969]

21. 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]

22. Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, Kumanishi T. (1999) Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci, 2 (12): 1091-7. [PMID:10570486]

23. 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 USA, 92 (14): 6542-6. [PMID:7604029]

24. 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]

25. Krapivinsky G, Gordon EA, Wickman K, Velimirović B, Krapivinsky L, Clapham DE. (1995) The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature, 374 (6518): 135-41. [PMID:7877685]

26. Kubo Y, Reuveny E, Slesinger PA, Jan YN, Jan LY. (1993) Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Nature, 364 (6440): 802-6. [PMID:8355805]

27. Kurachi Y. (1995) G protein regulation of cardiac muscarinic potassium channel. Am J Physiol, 269 (4 Pt 1): C821-30. [PMID:7485449]

28. Leaney JL. (2003) Contribution of Kir3.1, Kir3.2A and Kir3.2C subunits to native G protein-gated inwardly rectifying potassium currents in cultured hippocampal neurons. Eur J Neurosci, 18 (8): 2110-8. [PMID:14622172]

29. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, Romey G, Barhanin J, Lazdunski M. (1995) Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem, 270 (48): 28660-7. [PMID:7499385]

30. Lewohl JM, Wilson WR, Mayfield RD, Brozowski SJ, Morrisett RA, Harris RA. (1999) G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci, 2 (12): 1084-90. [PMID:10570485]

31. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. (1987) The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature, 325 (6102): 321-6. [PMID:2433589]

32. 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]

33. Lüscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA. (1997) G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron, 19 (3): 687-95. [PMID:9331358]

34. 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]

35. 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]

36. Nishida M, Cadene M, Chait BT, MacKinnon R. (2007) Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J, 26 (17): 4005-15. [PMID:17703190]

37. Nishida M, MacKinnon R. (2002) Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell, 111 (7): 957-65. [PMID:12507423]

38. Padgett CL, Lalive AL, Tan KR, Terunuma M, Munoz MB, Pangalos MN, Martínez-Hernández J, Watanabe M, Moss SJ, Luján R et al.. (2012) Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. Neuron, 73 (5): 978-89. [PMID:22405207]

39. Pegan S, Arrabit C, Zhou W, Kwiatkowski W, Collins A, Slesinger PA, Choe S. (2005) Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci, 8 (3): 279-87. [PMID:15723059]

40. Peleg S, Varon D, Ivanina T, Dessauer CW, Dascal N. (2002) G(alpha)(i) controls the gating of the G protein-activated K(+) channel, GIRK. Neuron, 33 (1): 87-99. [PMID:11779482]

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

42. Reuveny E, Slesinger PA, Inglese J, Morales JM, Iñiguez-Lluhi JA, Lefkowitz RJ, Bourne HR, Jan YN, Jan LY. (1994) Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits. Nature, 370 (6485): 143-6. [PMID:8022483]

43. Saitoh O, Masuho I, Terakawa I, Nomoto S, Asano T, Kubo Y. (2001) Regulator of G protein signaling 8 (RGS8) requires its NH2 terminus for subcellular localization and acute desensitization of G protein-gated K+ channels. J Biol Chem, 276 (7): 5052-8. [PMID:11087736]

44. Schoots O, Yue KT, MacDonald JF, Hampson DR, Nobrega JN, Dixon LM, Van Tol HH. (1996) Cloning of a G protein-activated inwardly rectifying potassium channel from human cerebellum. Brain Res Mol Brain Res, 39 (1-2): 23-30. [PMID:8804710]

45. Schreibmayer W, Dessauer CW, Vorobiov D, Gilman AG, Lester HA, Davidson N, Dascal N. (1996) Inhibition of an inwardly rectifying K+ channel by G-protein alpha-subunits. Nature, 380 (6575): 624-7. [PMID:8602262]

46. Torrecilla M, Quillinan N, Williams JT, Wickman K. (2008) Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: a study of GIRK-knockout mice. Eur J Neurosci, 28 (3): 618-24. [PMID:18702733]

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

48. Wickman KD, Iñiguez-Lluhl JA, Davenport PA, Taussig R, Krapivinsky GB, Linder ME, Gilman AG, Clapham DE. (1994) Recombinant G-protein beta gamma-subunits activate the muscarinic-gated atrial potassium channel. Nature, 368 (6468): 255-7. [PMID:8145826]

49. Wieting JM, Vadukoot AK, Sharma S, Abney KK, Bridges TM, Daniels JS, Morrison RD, Wickman K, Weaver CD, Hopkins CR. (2017) Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators. ACS Chem Neurosci, 8 (9): 1873-1879. [PMID:28697302]

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