Molecule Information

General Information of the Molecule (ID: Mol01851)

• Name: G protein-activated inward rectifier potassium channel 4 (GIRK4) ,Homo sapiens
• Synonyms: G protein-activated inward rectifier potassium channel 4; GIRK-4; Cardiac inward rectifier; CIR; Heart KATP channel; Inward rectifier K(+) channel Kir3.4); IRK-4; KATP-1; Potassium channel; inwardly rectifying subfamily J member 5; KCNJ5
• Molecule Type: Protein
• Gene Name: GIRK4
• Gene ID: 3762
• Location: chr11:128,891,356-128,921,163[+]
• Sequence:
  MAGDSRNAMNQDMEIGVTPWDPKKIPKQARDYVPIATDRTRLLAEGKKPRQRYMEKSGKC
  NVHHGNVQETYRYLSDLFTTLVDLKWRFNLLVFTMVYTVTWLFFGFIWWLIAYIRGDLDH
  VGDQEWIPCVENLSGFVSAFLFSIETETTIGYGFRVITEKCPEGIILLLVQAILGSIVNA
  FMVGCMFVKISQPKKRAETLMFSNNAVISMRDEKLCLMFRVGDLRNSHIVEASIRAKLIK
  SRQTKEGEFIPLNQTDINVGFDTGDDRLFLVSPLIISHEINQKSPFWEMSQAQLHQEEFE
  VVVILEGMVEATGMTCQARSSYMDTEVLWGHRFTPVLTLEKGFYEVDYNTFHDTYETNTP
  SCCAKELAEMKREGRLLQYLPSPPLLGGCAEAGLDAEAEQNEEDEPKGLGGSREARGSV
• 3D-structure: PDB ID: 8VGN; Classification: Membrane protein/immune system; Method: Electron microscopy; Resolution: 2.50 Å
• Function: This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium.
• Uniprot ID: KCNJ5_HUMAN
• Ensembl ID: ENSG00000120457
• HGNC ID: HGNC:6266

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Amiloride

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Adrenal adenoma [ICD-11: 2F3Z.0] [1]

• Sensitive Disease: Adrenal adenoma [ICD-11: 2F3Z.0]
• Sensitive Drug: Amiloride
• Molecule Alteration: Missense mutation; p.L168R (c.503T>G)
• Experimental Note: Identified from the Human Clinical Data

Rituximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female B-NDG mice (5-7 weeks old) , with PDK4-overexpressing OCI-ly8 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression

References

• Ref 1: Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomasEndocrinology. 2014 Apr;155(4):1353-62. doi: 10.1210/en.2013-1944. Epub 2014 Feb 7.
• Ref 2: Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20. Cancer Sci. 2021 Sep;112(9):3585-3597.