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There are 800 genes in this family in the mammalian genome

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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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Presentation Transcript
slide1
G-Protein Coupled Receptors

There are 800 genes in this family in the mammalian genome

slide3
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

slide4
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

slide5
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

slide6
Krebs Cycle

GPR91

GPR99

slide7
Highest expression is in the Kidney

GPR91

GPR99

Mostly Proximal Tubule and JGA Mostly Distal Tubule

slide8
Succ

a-KG

slide13
In Isolated Perfused JGA :

Perfusion of Succinate increases renin release

Fluorocitrate

slide14
Renin release in Isolated Perfused JGA

Succinate in the bath is faster than high glucose

slide19
High Glucose and Succinate increase cell Calcium via GPR91 in isolated glomerular endothelial cells
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