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Kir3.4

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Target not currently curated in GtoImmuPdb

Target id: 437

Nomenclature: Kir3.4

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 1 419 11q24.3 KCNJ5 potassium inwardly rectifying channel subfamily J member 5 29
Mouse 2 1 419 9 17.65 cM Kcnj5 potassium inwardly-rectifying channel, subfamily J, member 5 22,33
Rat 2 1 419 8q21 Kcnj5 potassium inwardly-rectifying channel, subfamily J, member 5 20
Previous and Unofficial Names Click here for help
potassium inwardly rectifying channel subfamily J member 5 | cardiac inward rectifier | CIR | GIRK4 | G protein-activated inward rectifier potassium channel 4 | heart KATP channel | IKACh | inward rectifier K(+) channel Kir3.4 | KATP1 | LQT13 | potassium channel, inwardly rectifying subfamily J, member 5 | potassium inwardly-rectifying channel | potassium voltage-gated channel subfamily J member 5
Database Links Click here for help
Alphafold P48544 (Hs), P48545 (Mm), P48548 (Rn)
CATH/Gene3D 2.60.40.1400
ChEMBL Target CHEMBL1914278 (Hs), CHEMBL3714708 (Rn)
Ensembl Gene ENSG00000120457 (Hs), ENSMUSG00000032034 (Mm), ENSRNOG00000033796 (Rn)
Entrez Gene 3762 (Hs), 16521 (Mm), 29713 (Rn)
Human Protein Atlas ENSG00000120457 (Hs)
KEGG Gene hsa:3762 (Hs), mmu:16521 (Mm), rno:29713 (Rn)
OMIM 600734 (Hs)
Orphanet ORPHA235181 (Hs)
Pharos P48544 (Hs)
RefSeq Nucleotide NM_000890 (Hs), NM_010605 (Mm), NM_017297 (Rn)
RefSeq Protein NP_000881 (Hs), NP_034735 (Mm), NP_058993 (Rn)
UniProtKB P48544 (Hs), P48545 (Mm), P48548 (Rn)
Wikipedia KCNJ5 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Kir3.1 20
Kir3.2 7,10,22
Kir3.3 10
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
Kir3.4 functions principally with Kir3.1, forming a channel often known as IKACh [20], the major functional assembly in the heart.
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+ [15.0 - 30.0 pS]
References:  20
Ion Selectivity and Conductance Comments
Kir3.1/3.4 heteromer (K+, 36.6pS [20]).

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 - - - 1x10-2 - 2x10-1 -120.0 – -70.0 15,23
⤷ Conc range: 1x10-2 - 2x10-1 M [15,23]
Holding voltage: -120.0 – -70.0 mV
arachidonic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Agonist - - 1x10-5 - 1x10-4 -80.0 14
⤷ Conc range: 1x10-5 - 1x10-4 M [14]
Holding voltage: -80.0 mV
fingolimod Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Mm Agonist - - 1x10-8 - 1x10-7 -90.0 19
⤷ Conc range: 1x10-8 - 1x10-7 M [19]
Holding voltage: -90.0 mV
Na+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 1.4 pEC50 - -80.0 30
⤷ pEC50 1.4 [30]
Holding voltage: -80.0 mV
PIP2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs - - - - - 4,9
⤷ [4,9]
View species-specific activator tables
Activator Comments
All the activators indicated above were assessed using Kir3.1/3.4 (IKACh) channel, although Kir3.4 can also form homomeric channels with rare, brief openings [7,20].

The Kir3.1/3.4 channel is activated by G-protein coupled receptors linked to Gαi/Gβγ heterotrimers. For example, activation of acetylcholine M2 or M4 receptors, purinergic or somatostatin receptors result in direct Gβγ activation of the channel. Gαi does not directly activate the channel, and may have some inhibitory effect, although whether this is direct or indirect is not clear. Gβγ dimers bind Kir3.1/3.4 channels with a pKd of 7.3 [21]. It important to note that the Xenopus homologue (U42207) of mammalian Kir3.4 is called Kir3.5 [8].
Gating inhibitors Click here for help
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
phorbol 12-myristate 13-acetate Small molecule or natural product Click here for species-specific activity table Rn - - - 3x10-8 -80.0 25
⤷ Conc range: 3x10-8 M [25]
Holding voltage: -80.0 mV
Gating Inhibitor Comments
The action of PMA is via activation of PKC [25] and is studied in Kir3.1/3.4 heteromers.
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
NIP-142 Small molecule or natural product Hs Antagonist - - 1x10-6 - 1x10-4 -120.0 – 50.0 26
⤷ Conc range: 1x10-6 - 1x10-4 M [26]
Holding voltage: -120.0 – 50.0 mV
tertiapin-Q Peptide Click here for species-specific activity table Rn Antagonist 8.1 pKi - -80.0 – 80.0 13
⤷ pKi 8.1 [13]
Holding voltage: -80.0 – 80.0 mV
imipramine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 4.5 pEC50 - -70.0 16
⤷ pEC50 4.5 [16]
Holding voltage: -70.0 mV
Cs+ Click here for species-specific activity table Rn Antagonist 4.0 pEC50 - -80.0 20
⤷ pEC50 4.0 [20]
Holding voltage: -80.0 mV
Ba2+ Click here for species-specific activity table Rn Antagonist 3.3 pEC50 - -80.0 20
⤷ pEC50 3.3 [20]
Holding voltage: -80.0 mV
tertiapin-Q Peptide N/A Antagonist 7.9 pIC50 - - 12
⤷ pIC50 7.9 Kir3.1/3.4 [12]
AZD2927 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs - 5.9 pIC50 - - 3
⤷ pIC50 5.9 (IC50 1.3x10-6 M) [3]
desipramine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 4.3 pIC50 - -70.0 16
⤷ pIC50 4.3 [16]
Holding voltage: -70.0 mV
amitriptyline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 3.6 pIC50 - -70.0 16
⤷ pIC50 3.6 [16]
Holding voltage: -70.0 mV
clomipramine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 3.6 pIC50 - -70.0 16
⤷ pIC50 3.6 [16]
Holding voltage: -70.0 mV
maprotiline Small molecule or natural product Approved drug Click here for species-specific activity table Mm Antagonist 3.5 pIC50 - -70.0 16
⤷ pIC50 3.5 [16]
Holding voltage: -70.0 mV
nortriptyline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 3.4 pIC50 - -70.0 16
⤷ pIC50 3.4 [16]
Holding voltage: -70.0 mV
View species-specific channel blocker tables
Channel Blocker Comments
These compounds have been tested with the Kir3.1/3.4 heterodimer. This channel is also inhibited by peptides and proteins that bind Gβγ [1,11,17].
Tissue Distribution Click here for help
Heart (atria > ventricle).
Species:  Mouse
Technique:  In situ hybridisation
References:  31
Pancreatic alpha cells.
Species:  Mouse
Technique:  Immunohistochemistry
References:  34
Brain (deep cortical pyramidal neurons, endopiriform nucleus, claustrum of the insular cortex, ventromedial hypothalamic nucleus, parafascicular and paraventricular thalamic nuclei, inferior olive nucleus, vestibular nucleus > laterodorsal and lateral posterior thalamic nuclei). Restricted to subsets of neurons in the hippocampus (dentate gyrus), globus pallidus, superior colliculus, medial vestibular and dorsal tegmental nuclei, anterior olfactory nuceus and lateral cerebellar nuclei.
Species:  Mouse
Technique:  In situ hybridisation
References:  31
Brain: Restricted to specific populations in the neocortex (layer IV), septum (globus pallidus, ventral striatum, ventral pallidum), thalamus (medial habenula), basal forebrain (nucleus of the diagonal band) and cerebellum (purkinje cells).
Species:  Rat
Technique:  Immunohistochemistry
References:  27
Functional Assays Click here for help
Patch clamp.
Species:  Rat
Tissue:  Atria.
Response measured:  Current of the Kir3.1/3.4 heteromeric channel.
References:  5,20,24,28
Patch clamp.
Species:  Mouse
Tissue:  Atria.
Response measured:  Current of the Kir3.1/3.4 heteromeric channel.
References:  19
Electrical activity of normal and paced heart in Kir3.4-/- mice: resistance of Kir3.4-/- mice to induced atrial fibrillation.
Species:  Mouse
Tissue:  Heart
Response measured:  Electrocardiography.
References:  18
Patch clamp.
Species:  Rat
Tissue:  Xenopus laevis oocytes
Response measured:  Current of channels consisting of endogenous Xenopus Kir3.5 and rat Kir3.1.
References:  8
Physiological Functions Click here for help
The diving reflex in mammals and birds evoked by submerging the face in water (bradycardia).
Species:  None
Tissue:  Heart.
References: 
Vagal-induced (parasympathetic) slowing of the heart rate by muscarinic acetylcholine (M2), adenosine and somatostatin receptors.
Species:  Mouse
Tissue:  Heart
References:  32
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
Kcnj5tm1Clph Kcnj5tm1Clph/Kcnj5tm1Clph
either: (involves: 129X1/SvJ) or (involves: 129X1/SvJ * C57BL/6J)		 MGI:104755  MP:0001629 abnormal heart rate PMID: 9459446 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Cardiac arrhythmia
Role:  Vagus nerve activation of muscarinic (M2) receptors activate Kir3.1/3.4 (IKACh) channels typically causing fainting, but also the diving reflex.
Drugs:  Atropine
Side effects:  Anticholinergic (dry mouth, glaucoma).
Therapeutic use:  Bradycardia.
References:  2
Disease:  Cardiac arrhythmia
Role:  Supraventricular tachycardias caused by re-entrant circuits.
Drugs:  Adenosine (activation of Kir3.1/3.4 via purinergic receptors).
Side effects:  Flushing, rapid heart rate, nausea.
Therapeutic use:  To restore normal sinus rhythm.
References:  2
Disease:  Familial hyperaldosteronism type III
OMIM: 613677
Orphanet: ORPHA251274
Disease:  Long QT syndrome 13; LQT13
Synonyms: Long QT syndrome [Disease Ontology: DOID:2843]
Romano-Ward syndrome [Orphanet: ORPHA101016]
Disease Ontology: DOID:2843
OMIM: 613485
Orphanet: ORPHA101016
Clinically-Relevant Mutations and Pathophysiology Comments
In a genome-wide screen autosomal dominant migraine with aura has been found to link to a locus on 11q24. This region contains several candidate genes, including Kir1.1 and Kir3.4 [6].
General Comments
The Xenopus homologue (U42207) of mammalian Kir3.4 is called Kir3.5.

References

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1. Appleyard SM, Celver J, Pineda V, Kovoor A, Wayman GA, Chavkin C. (1999) Agonist-dependent desensitization of the kappa opioid receptor by G protein receptor kinase and beta-arrestin. J Biol Chem, 274 (34): 23802-7. [PMID:10446141]

2. Armstrong A, Clapham DE. (2007) Pharmacology of Cardiac Rhythm. In Principles of pharmacology: the pathophysiologic basis of drug therapy (2nd edition). Edited by Dolan DE, Tashjian AH, Armstrong EJ, Armstrong AW (Lipponcott Williams and Wilkins) 307-324. [ISBN:0781783550]

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

4. Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B. (1998) PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science, 282 (5391): 1141-4. [PMID:9804555]

5. Breitwieser GE, Szabo G. (1985) Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature, 317 (6037): 538-40. [PMID:2413368]

6. Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC. (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet, 12 (19): 2511-7. [PMID:12915447]

7. Corey S, Clapham DE. (1998) Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers. J Biol Chem, 273 (42): 27499-504. [PMID:9765280]

8. 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]

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, 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]

11. Jin W, Brown S, Roche JP, Hsieh C, Celver JP, Kovoor A, Chavkin C, Mackie K. (1999) Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J Neurosci, 19 (10): 3773-80. [PMID:10234009]

12. 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]

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

14. Kim D, Lewis DL, Graziadei L, Neer EJ, Bar-Sagi D, Clapham DE. (1989) G-protein beta gamma-subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature, 337 (6207): 557-60. [PMID:2492640]

15. 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]

16. Kobayashi T, Washiyama K, Ikeda K. (2004) Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. Neuropsychopharmacology, 29 (10): 1841-51. [PMID:15150531]

17. Kovoor A, Celver JP, Wu A, Chavkin C. (1998) Agonist induced homologous desensitization of mu-opioid receptors mediated by G protein-coupled receptor kinases is dependent on agonist efficacy. Mol Pharmacol, 54 (4): 704-11. [PMID:9765514]

18. Kovoor P, Wickman K, Maguire CT, Pu W, Gehrmann J, Berul CI, Clapham DE. (2001) Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol, 37 (8): 2136-43. [PMID:11419900]

19. Koyrakh L, Roman MI, Brinkmann V, Wickman K. (2005) The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I. Am J Transplant, 5 (3): 529-36. [PMID:15707407]

20. 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]

21. Krapivinsky G, Krapivinsky L, Wickman K, Clapham DE. (1995) G beta gamma binds directly to the G protein-gated K+ channel, IKACh. J Biol Chem, 270 (49): 29059-62. [PMID:7493925]

22. 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]

23. 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]

24. 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]

25. Mao J, Wang X, Chen F, Wang R, Rojas A, Shi Y, Piao H, Jiang C. (2004) Molecular basis for the inhibition of G protein-coupled inward rectifier K(+) channels by protein kinase C. Proc Natl Acad Sci USA, 101 (4): 1087-92. [PMID:14732702]

26. Matsuda T, Takeda K, Ito M, Yamagishi R, Tamura M, Nakamura H, Tsuruoka N, Saito T, Masumiya H, Suzuki T et al.. (2005) Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium. J Pharmacol Sci, 98 (1): 33-40. [PMID:15879679]

27. Murer G, Adelbrecht C, Lauritzen I, Lesage F, Lazdunski M, Agid Y, 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 (2): 345-57. [PMID:9284339]

28. Pfaffinger PJ, Martin JM, Hunter DD, Nathanson NM, Hille B. (1985) GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature, 317 (6037): 536-8. [PMID:2413367]

29. Spauschus A, Lentes KU, Wischmeyer E, Dissmann E, Karschin C, Karschin A. (1996) A G-protein-activated inwardly rectifying K+ channel (GIRK4) from human hippocampus associates with other GIRK channels. J Neurosci, 16 (3): 930-8. [PMID:8558261]

30. Sui JL, Chan KW, Logothetis DE. (1996) Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism. J Gen Physiol, 108 (5): 381-91. [PMID:8923264]

31. Wickman K, Karschin C, Karschin A, Picciotto MR, Clapham DE. (2000) Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. J Neurosci, 20 (15): 5608-15. [PMID:10908597]

32. Wickman K, Nemec J, Gendler SJ, Clapham DE. (1998) Abnormal heart rate regulation in GIRK4 knockout mice. Neuron, 20 (1): 103-14. [PMID:9459446]

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

34. Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M, Kurachi Y. (1999) Somatostatin induces hyperpolarization in pancreatic islet alpha cells by activating a G protein-gated K+ channel. FEBS Lett, 444 (2-3): 265-9. [PMID:10050772]

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