| Gene | [KCNJ3](/genes/kcnj3) |
| UniProt ID | [P48051](https://www.uniprot.org/uniprot/P48051) |
| PDB Structures | [6VKG](https://www.rcsb.org/structure/6VKG), [6VIC](https://www.rcsb.org/structure/6VIC) |
| Molecular Weight | 56.7 kDa |
| Amino Acids | 501 |
| Subcellular Location | Plasma membrane |
| Protein Family | Inward rectifier potassium channel (Kir) family |
G protein-activated inward rectifier potassium channel 1 (GIRK1), also known as Kir3.1 or KCNJ3, is a 56 kDa inward-rectifying potassium channel subunit that forms ligand-gated potassium channels activated by G protein-coupled receptors (GPCRs)[1]. Encoded by the KCNJ3 gene on chromosome 2q24.1, GIRK1 assembles with other GIRK subunits (GIRK2/KCNJ6, GIRK3/KCNJ9, GIRK4/KCNJ5) to form heterotetrameric channels that mediate slow inhibitory postsynaptic potentials in neurons[2].
GIRK channels are critical regulators of neuronal excitability, coupling inhibitory neurotransmitter receptors (GABA-B, M2 muscarinic, μ-opioid) to membrane hyperpolarization through direct Gβγ subunit binding[3]. In the nervous system, GIRK1-containing channels regulate action potential firing, neurotransmitter release, and synaptic plasticity, making them important players in neurological disorders including epilepsy, addiction, and neurodegenerative diseases[4].
GIRK1 forms homotetrameric or heterotetrameric channels with characteristic inward rectifier architecture[5]:
GIRK1-containing channels mediate slow inhibitory postsynaptic potentials[6]:
GIRK channels provide tonic inhibitory tone via[7]:
GIRK1 channels influence synaptic function through[8]:
GIRK1 is coupled to multiple inhibitory receptor systems[9]:
GIRK1 function is altered in AD[10]:
GIRK1 roles in basal ganglia circuitry[11]:
GIRK1 dysfunction in seizure disorders[12]:
GIRK1 in substance use disorders[13]:
Positive modulators (GIRK activators)[14]:
Negative modulators (GIRK inhibitors)[15]:
Epilepsy treatment[16]:
Addiction therapy[17]:
Pain management[18]:
| Interactor | Function | Disease Relevance |
|---|---|---|
| GIRK2/KCNJ6 | Heterotetramer formation | Neuronal GIRK channels |
| GIRK3/KCNJ9 | Heterotetramer formation | Neuronal/pancreatic channels |
| GIRK4/KCNJ5 | Heterotetramer formation | Cardiac/neuronal channels |
| Gβγ subunits | Direct activation | GPCR signaling |
| PIP2 | Channel gating | Membrane signaling |
| GABA-B R2 | Receptor coupling | Inhibitory signaling |
| μ-opioid receptor | Receptor coupling | Analgesia |
| M2 receptor | Receptor coupling | Cholinergic signaling |
| PDZ proteins | Scaffolding | Synaptic localization |
GIRK1 is a critical component of neuronal inhibitory signaling, coupling G protein-coupled receptors to membrane hyperpolarization through potassium efflux. As a primary mediator of slow inhibitory postsynaptic potentials, GIRK1-containing channels regulate neuronal excitability, synaptic plasticity, and network synchronization. Dysregulation of GIRK1 function contributes to epilepsy, addiction, and neurodegenerative diseases, making GIRK modulation an attractive therapeutic target.
Kubo Y, Reuveny E, Slesinger PA, et al. Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Nature. 1993. ↩︎
Kofuji P, Davidson N, Lester HA. Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by Gβγ subunits and function as heteromultimers. PNAS. 1995. ↩︎
Wickman KD, Iñiguez-Lluhl JA, Davenport PA, et al. Recombinant G-protein βγ-subunits activate the muscarinic-gated atrial potassium channel. Nature. 1994. ↩︎
Lüscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nature Reviews Neuroscience. 2010. ↩︎
Whorton MR, MacKinnon R. Crystal structure of the mammalian GIRK2-βγ G-protein complex. Nature. 2013. ↩︎
Lüscher C, Jan LY, Stoffel M, et al. [G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons](https://doi.org/10.1016/S0896-6273(00). Neuron. 1997. ↩︎
Chen SC, Ehrlich BE. G protein-gated inwardly rectifying K+ channels and neuronal excitability. Physiology. 2018. ↩︎
Chung HJ, Jan YN, Jan LY. Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains. PNAS. 2006. ↩︎
marker Y, Karschin C, Ross EM, et al. G protein-gated K+ channels: conserved subunit composition. Journal of Biological Chemistry. 1996. ↩︎
Ohno M, Sametsky EA, Silva AJ, Disterhoft JF. Differential effects of α-CaMKII mutation on hippocampal-dependent learning and memory in young and aged mice. Journal of Neuroscience. 2006. ↩︎
Kuzhikandathil EV, Oxford GS. Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-23390) directly inhibits G protein-coupled inwardly rectifying potassium channels. Molecular Pharmacology. 2002. ↩︎
Millichap JJ, Liu HL, Puri R, et al. KCNJ3 mutations in epilepsy. Annals of Neurology. 2016. ↩︎
Labouèbe G, Lomazzi M, Cruz HG, et al. RGS2 modulates coupling between GABA-B receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nature Neuroscience. 2007. ↩︎
Kaufmann K, Romaine I, Days E, et al. ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in rodents. ACS Chemical Neuroscience. 2013. ↩︎
Jin W, Lu Z. A novel high-affinity inhibitor for inward-rectifier K+ channels. Biochemistry. 1998. ↩︎
Signorini S, Liao YJ, Duncan SA, et al. Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. PNAS. 1997. ↩︎
Torrecilla M, Marker CL, Cintora SC, et al. G-protein-gated inwardly rectifying potassium channels contain DLP4 motif required for behavioral effects of ethanol. Nature Neuroscience. 2008. ↩︎
Marker CL, Laitinen K, Arar M, Wickman K. GIRK1 and GIRK2 in the brain: implications for analgesia. Pain. 2010. ↩︎