Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT3RRJN)

• DOT Name: Cardiac phospholamban (PLN)
• Synonyms: PLB
• Gene Name: PLN
• Related Disease:
  Dilated cardiomyopathy 1P
  Intrinsic cardiomyopathy
  Hypertrophic cardiomyopathy 18
  Arrhythmogenic right ventricular cardiomyopathy
  Obsolete familial isolated dilated cardiomyopathy
• UniProt ID: PPLA_HUMAN
• PDB ID: 1PLP; 1ZLL; 2HYN; 6Y40; 7E0Z; 7E11; 7E12
• Pfam ID: PF04272
• Sequence: MEKVQYLTRSAIRRASTIEMPQQARQKLQNLFINFCLILICLLLICIIVMLL
• Function: Reversibly inhibits the activity of ATP2A2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN. ATP2A2 inhibition is alleviated by PLN phosphorylation. Controls intracellular Ca(2+) levels in elongated spermatids. May play a role in germ cell differentiation.
• Tissue Specificity: Heart muscle (at protein level).
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Thyroid hormone sig.ling pathway (hsa04919)
  Dilated cardiomyopathy (hsa05414)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Ion transport by P-type ATPases (R-HSA-936837)
  Ion homeostasis (R-HSA-5578775)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy 1P	DISIWEP5	Definitive	Autosomal dominant	[1]
Intrinsic cardiomyopathy	DISYBB39	Definitive	Autosomal dominant	[2]
Hypertrophic cardiomyopathy 18	DISJ7BPQ	Strong	Autosomal dominant	[3]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Moderate	Autosomal dominant	[2]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dobutamine	DMD1B8Z	Approved	Cardiac phospholamban (PLN) affects the response to substance of Dobutamine.	[11]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cardiac phospholamban (PLN).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cardiac phospholamban (PLN).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cardiac phospholamban (PLN).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cardiac phospholamban (PLN).	[8]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Cardiac phospholamban (PLN).	[9]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Cardiac phospholamban (PLN).	[10]

References

• [1] A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93. doi: 10.1073/pnas.0510519103. Epub 2006 Jan 23.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med. 2019 Feb;12(2):e002460. doi: 10.1161/CIRCGEN.119.002460.
• [4] Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003 Feb 28;299(5611):1410-3. doi: 10.1126/science.1081578.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [10] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [11] Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats. J Clin Invest. 2004 Mar;113(5):727-36. doi: 10.1172/JCI18716.