Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2PEJDO)

• DOT Name: Extracellular calcium-sensing receptor (CASR)
• Synonyms: CaR; CaSR; hCasR; Parathyroid cell calcium-sensing receptor 1; PCaR1
• Gene Name: CASR
• Related Disease:
  Autosomal dominant hypocalcemia 1
  Familial hypocalciuric hypercalcemia 1
  Neonatal severe primary hyperparathyroidism
  Autosomal dominant hypocalcemia
  Epilepsy
  Epilepsy, idiopathic generalized, susceptibility to, 8
• UniProt ID: CASR_HUMAN
• PDB ID: 5FBH; 5FBK; 5K5S; 5K5T; 7DTT; 7DTU; 7DTV; 7DTW; 7E6T; 7E6U; 7M3E; 7M3F; 7M3G; 7M3J; 7SIL; 7SIM; 7SIN; 8WPG; 8WPU
• Pfam ID: PF00003 ; PF01094 ; PF07562
• Sequence:
  MAFYSCCWVLLALTWHTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQDLKSRPESVEC
  IRYNFRGFRWLQAMIFAIEEINSSPALLPNLTLGYRIFDTCNTVSKALEATLSFVAQNKI
  DSLNLDEFCNCSEHIPSTIAVVGATGSGVSTAVANLLGLFYIPQVSYASSSRLLSNKNQF
  KSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFS
  ELISQYSDEEEIQHVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWA
  SSSLIAMPQYFHVVGGTIGFALKAGQIPGFREFLKKVHPRKSVHNGFAKEFWEETFNCHL
  QEGAKGPLPVDTFLRGHEESGDRFSNSSTAFRPLCTGDENISSVETPYIDYTHLRISYNV
  YLAVYSIAHALQDIYTCLPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTNNMGEQVTFD
  ECGDLVGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFS
  NCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACNKCPDDFWSNENHTSCIA
  KEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLC
  CFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWG
  LNLQFLLVFLCTFMQIVICVIWLYTAPPSSYRNQELEDEIIFITCHEGSLMALGFLIGYT
  CLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIA
  ILAASFGLLACIFFNKIYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRKRSS
  SLGGSTGSTPSSSISSKSNSEDPFPQPERQKQQQPLALTQQEQQQQPLTLPQQQRSQQQP
  RCKQKVIFGSGTVTFSLSFDEPQKNAMAHRNSTHQNSLEAQKSSDTLTRHEPLLPLQCGE
  TDLDLTVQETGLQGPVGGDQRPEVEDPEELSPALVVSSSQSFVISGGGSTVTENVVNS
• Function: G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis. Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation.
• Tissue Specificity: Expressed in the temporal lobe, frontal lobe, parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung, liver, heart, skeletal muscle, placenta.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant hypocalcemia 1	DISSOX8L	Definitive	Autosomal dominant	[1]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Definitive	Autosomal dominant	[1]
Neonatal severe primary hyperparathyroidism	DISOJ4ON	Definitive	Autosomal recessive	[1]
Autosomal dominant hypocalcemia	DISW4TUE	Supportive	Autosomal dominant	[2]
Epilepsy	DISBB28L	Disputed	Autosomal dominant	[1]
Epilepsy, idiopathic generalized, susceptibility to, 8	DISFQI6J	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Extracellular calcium-sensing receptor (CASR).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Extracellular calcium-sensing receptor (CASR).	[5]
Amikacin	DM5PDRB	Approved	Amikacin increases the activity of Extracellular calcium-sensing receptor (CASR).	[6]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Extracellular calcium-sensing receptor (CASR).	[7]

References

• [1] 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.
• [2] A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia. J Clin Endocrinol Metab. 1999 Jan;84(1):363-6. doi: 10.1210/jcem.84.1.5385.
• [3] An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol. 2008 Aug;64(2):158-67. doi: 10.1002/ana.21428.
• [4] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Amikacin-induced type 5 Bartter-like syndrome with severe hypocalcemia. J Postgrad Med. 2009 Jul-Sep;55(3):208-10. doi: 10.4103/0022-3859.57407.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.