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There are 800 genes in this family in the mammalian genome

G-Protein Coupled Receptors. There are 800 genes in this family in the mammalian genome. Orphan Receptors in the GPCR family. Rhodopsin and b-adrenergic receptor found to be homologous “Artisanal Period”: Using known ligands to find their GPCR’s

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There are 800 genes in this family in the mammalian genome

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  1. G-Protein Coupled Receptors There are 800 genes in this family in the mammalian genome

  2. Orphan Receptors in the GPCR family Rhodopsin and b-adrenergic receptor found to be homologous “Artisanal Period”: Using known ligands to find their GPCR’s dopamine, adenosine; angiotensin, vasopressin etc “De-orphanisation” Using GPCR to find new transmitters e.g. nociceptin, ghrellin Industrial approach, many ligands and receptors identified olfactory ligands, taste receptors, H+, Ca++ Still; the majority of GPCR do not have known ligands; so they have been given numbers

  3. De-orphanization Protocols Many industrial approaches but most depend on the following Express GPCR of interest in a cell line which has the requisite signaling system, e.g. increase in Ca Use extracts of organs or blood to see if they activate the signal Purify the fraction that does it using this assay

  4. Tularik Co, wanted to find the ligands for GPCR 91, and GPCR 99 They are homologous to the Purinergic (ATP) receptors But after much search the activity in the kidney turned out to be Succinate for GPR91 and a-ketoglutarate for GPR99 Nature. 2004 ;429:188-93

  5. Krebs Cycle GPR91 GPR99

  6. Highest expression is in the Kidney GPR91 GPR99 Mostly Proximal Tubule and JGA Mostly Distal Tubule

  7. Succ a-KG

  8. Normal Nx

  9. Isolated Perfused JGA

  10. In Isolated Perfused JGA : High Glucose increases renin release

  11. In Isolated Perfused JGA : Perfusion of Succinate increases renin release Fluorocitrate

  12. Renin release in Isolated Perfused JGA Succinate in the bath is faster than high glucose

  13. Succinate Levels in Diabetic Urine and Kidneys

  14. Renin Release from Isolated perfused JGA preparation

  15. GPR91RECA-1 Merged

  16. High Glucose and Succinate increase cell Calcium in isolated endothelial cells

  17. High Glucose and Succinate increase cell Calcium via GPR91 in isolated glomerular endothelial cells

  18. High Glucose or Succinate increase cell Ca In isolated glomeruli

  19. High Succinate increase PGE2 production

  20. Diabetes increases renin granule content only in GPR91+ mice Control STZ Diabetes +/+ -/-

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