Nomenclature: Kir3.4

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. 

Contents

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 1 419 11q24 KCNJ5 potassium inwardly-rectifying channel, subfamily J, member 5 25
Mouse 2 1 419 9 A4 Kcnj5 potassium inwardly-rectifying channel, subfamily J, member 5 18,29
Rat 2 1 419 8q21 Kcnj5 potassium inwardly-rectifying channel, subfamily J, member 5 16
Previous and Unofficial Names
GIRK4
KCNJ5
KATP
IKACh
CIR
Kir3.4
KATP1
LQT13
MGC93525
G protein-activated inward rectifier potassium channel 4
GIRK-4
KATP-1
cardiac inward rectifier
heart KATP channel
inward rectifier K(+) channel Kir3.4
potassium channel, inwardly rectifying subfamily J member 5
potassium inwardly-rectifying channel, subfamily J, member 5
Database Links
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Kir3.3 7
Kir3.2 5,7,18
Kir3.1 16
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 [16], the major functional assembly in the heart.
Functional Characteristics
G-protein-activated inward-rectifier current
Ion Selectivity and Conductance
Species:  Rat
Rank order:  K+ [15.0 - 30.0 pS]
References:  16
Ion Selectivity and Conductance Comments
Kir3.1/3.4 heteromer (K+, 36.6pS [16]).
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
ethanol Mm - - - 1x10-2 - 2x10-1 -120.0 – -70.0 11,19
Conc range: 1x10-2 - 2x10-1 M [11,19]
Holding voltage: -120.0 – -70.0 mV
arachidonic acid Rn Agonist - - 1x10-5 - 1x10-4 -80.0 10
Conc range: 1x10-5 - 1x10-4 M [10]
Holding voltage: -80.0 mV
fingolimod Mm Agonist - - 1x10-8 - 1x10-7 -90.0 15
Conc range: 1x10-8 - 1x10-7 M [15]
Holding voltage: -90.0 mV
Na+ Hs Agonist 1.4 pEC50 - -80.0 26
pEC50 1.4 [26]
Holding voltage: -80.0 mV
PIP2 Hs - - - - -
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 [5,16].

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 [17]. It important to note that the Xenopus homologue (U42207) of mammalian Kir3.4 is called Kir3.5 [6].
Gating inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
phorbol 12-myristate 13-acetate Rn - - - 3x10-8 -80.0 21
Conc range: 3x10-8 M [21]
Holding voltage: -80.0 mV
Gating Inhibitor Comments
The action of PMA is via activation of PKC [21] 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 Affinity Units Concentration range (M) Holding voltage (mV) Reference
NIP-142 Hs Antagonist - - 1x10-6 - 1x10-4 -120.0 – 50.0 22
Conc range: 1x10-6 - 1x10-4 M [22]
Holding voltage: -120.0 – 50.0 mV
tertiapin Rn Antagonist 8.1 pKi - -80.0 – 80.0 9
pKi 8.1 [9]
Holding voltage: -80.0 – 80.0 mV
imipramine Mm Antagonist 4.5 pEC50 - -70.0 12
pEC50 4.5 [12]
Holding voltage: -70.0 mV
Cs+ Rn Antagonist 4.0 pEC50 - -80.0 16
pEC50 4.0 [16]
Holding voltage: -80.0 mV
Ba2+ Rn Antagonist 3.3 pEC50 - -80.0 16
pEC50 3.3 [16]
Holding voltage: -80.0 mV
desipramine Mm Antagonist 4.3 pIC50 - -70.0 12
pIC50 4.3 [12]
Holding voltage: -70.0 mV
clomipramine Mm Antagonist 3.6 pIC50 - -70.0 12
pIC50 3.6 [12]
Holding voltage: -70.0 mV
amitriptyline Mm Antagonist 3.6 pIC50 - -70.0 12
pIC50 3.6 [12]
Holding voltage: -70.0 mV
maprotiline Mm Antagonist 3.5 pIC50 - -70.0 12
pIC50 3.5 [12]
Holding voltage: -70.0 mV
nortriptyline Mm Antagonist 3.4 pIC50 - -70.0 12
pIC50 3.4 [12]
Holding voltage: -70.0 mV
View species-specific channel blocker tables
Channel Blocker Comments
These compounds have been tested with th Kir3.1/3.4 heterodimer. This channel is also inhibited by peptides and proteins that bind Gβγ [1,8,13].
Tissue Distribution
Heart (atria > ventricle).
Species:  Mouse
Technique:  In situ hybridisation
References:  27
Pancreatic alpha cells.
Species:  Mouse
Technique:  Immunohistochemistry
References:  30
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:  27
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:  23
Functional Assays
Patch clamp.
Species:  Rat
Tissue:  Atria.
Response measured:  Current of the Kir3.1/3.4 heteromeric channel.
References:  3,16,20,24
Patch clamp.
Species:  Mouse
Tissue:  Atria.
Response measured:  Current of the Kir3.1/3.4 heteromeric channel.
References:  15
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:  14
Patch clamp.
Species:  Rat
Tissue:  Xenopus laevis oocytes
Response measured:  Current of channels consisting of endogenous Xenopus Kir3.5 and rat Kir3.1.
References:  6
Physiological Functions
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:  28
Phenotypes, Alleles and Disease Models 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
Disease:  Cardiac arrhythmia
Role: 
Drugs: 
Side effects:  Anticholinergic (dry mouth, glaucoma).
Therapeutic use:  Bradycardia.
References:  2
Mutations not determined
Disease:  Cardiac arrhythmia
Role: 
Drugs: 
Side effects:  Flushing, rapid heart rate, nausea.
Therapeutic use:  To restore normal sinus rhythm.
References:  2
Mutations not determined
Disease:  Long QT syndrome 13; LQT13
OMIM:  613485
Orphanet:  101016
References: 
Mutations not determined
Disease:  Hyperaldosteronism, familial, type III
OMIM:  613677
Orphanet:  251274
References: 
Mutations not determined
Clinically-Relevant Mutations and Pathophysiology Comments
In a genome-wide screen autosomal dominant migrane with aura has been found to link to a locus on 11q24. This region contains several candidate genes, including Kir1.1 and Kir3.4 [4].
General Comments
The Xenopus homologue (U42207) of mammalian Kir3.4 is called Kir3.5.

REFERENCES

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. Breitwieser GE, Szabo G. (1985) Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature317 (6037): 538-40. [PMID:2413368]

4. 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]

5. 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]

6. 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. Neuron16 (2): 423-9. [PMID:8789957]

7. 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]

8. 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]

9. Jin W, Lu Z. (1998) A novel high-affinity inhibitor for inward-rectifier K+ channels. Biochemistry37 (38): 13291-9. [PMID:9748337]

10. 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. Nature337 (6207): 557-60. [PMID:2492640]

11. 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]

12. Kobayashi T, Washiyama K, Ikeda K. (2004) Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. Neuropsychopharmacology29 (10): 1841-51. [PMID:15150531]

13. 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]

14. 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]

15. 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]

16. 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. Nature374 (6518): 135-41. [PMID:7877685]

17. 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]

18. 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]

19. 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]

20. 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. Nature325 (6102): 321-6. [PMID:2433589]

21. 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. U.S.A.101 (4): 1087-92. [PMID:14732702]

22. Matsuda T, Takeda K, Ito M, Yamagishi R, Tamura M, Nakamura H, Tsuruoka N, Saito T, Masumiya H, Suzuki T, Iida-Tanaka N, Itokawa-Matsuda M, Yamashita T, Tsuruzoe N, Tanaka H, Shigenobu K. (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]

23. 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. Neuroscience80 (2): 345-57. [PMID:9284339]

24. Pfaffinger PJ, Martin JM, Hunter DD, Nathanson NM, Hille B. (1985) GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature317 (6037): 536-8. [PMID:2413367]

25. 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]

26. 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]

27. 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]

28. Wickman K, Nemec J, Gendler SJ, Clapham DE. (1998) Abnormal heart rate regulation in GIRK4 knockout mice. Neuron20 (1): 103-14. [PMID:9459446]

29. Wickman K, Pu WT, Clapham DE. (2002) Structural characterization of the mouse Girk genes. Gene284 (1-2): 241-50. [PMID:11891065]

30. 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]

To cite this database page, please use the following:

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, Wade L. Pearson, Susumu Seino, Carol A. Vandenberg.
Inwardly rectifying potassium channels: Kir3.4. Last modified on 05/12/2013. Accessed on 25/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=437.

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