G-Protein Coupled Receptors
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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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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

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


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


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


Krebs Cycle 99

GPR91

GPR99


Highest expression is in the Kidney 99

GPR91

GPR99

Mostly Proximal Tubule and JGA Mostly Distal Tubule


Succ 99

a-KG


Normal 99

Nx



In Isolated Perfused JGA : 99High Glucose increases renin release


In Isolated Perfused JGA 99:

Perfusion of Succinate increases renin release

Fluorocitrate


Renin release in Isolated Perfused JGA 99

Succinate in the bath is faster than high glucose




GPR91 99RECA-1 Merged



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


High Glucose or Succinate increase cell Ca in isolated glomerular endothelial cells

In isolated glomeruli


High Succinate increase PGE2 production in isolated glomerular endothelial cells


Diabetes increases renin granule content only in GPR91+ mice in isolated glomerular endothelial cells

Control

STZ

Diabetes

+/+ -/-


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