Orphan Returning Home #ExpBio

Mar 30 2015 Published by under EB 2015

The kidneys provide half of our acid-base balance in the body, with the rest being performed by our lungs. Our pulmonary system regulates the intake and output of carbon dioxide, while the kidneys excrete acid and retain or generate bicarbonate, the primary buffer in the fluids outside of our cells.

It’s amazing how much of this process has been figured out over time. It takes a very complex system to regulate the balance of a critical component so tightly, yet we still find new systems to take into account.

Elucidating the Physiological Role of Gprc5c, a Novel Orphan GPCR in the Kidney. P Rajkumar and JL Pluznick

G protein coupled receptors (GPCRs) are a class of membrane bound molecules that sense signals outside a cell and then trigger other effects. This group found an orphan GPCR, one whose ligand (fancy science talk for the signal it senses). It was interesting, in part, because it is found abundantly within the kidney, at a comparable level to angiotensin receptors. Other investigators had developed an antibody to it, as well as a mouse with this gene knocked-out, making it an excellent target for further study.

The antibody showed lots of this protein, mostly in the apical or inside-membrane of proximal tubule cells. The proximal tubule of the kidney is a workhorse. These tubes have to reabsorb most of what gets filtered from the blood, since the kidney cleans blood by removing most stuff and then returning the good stuff. It’s similar to some organization shows on TV; instead of trying to take out unnecessary clutter, they start by clearing the room (filtration) and then putting only the useful, wanted things back in (proximal tubule reabsorption).

For their next step, they wanted to screen ligands, starting with known functions of the proximal tubule. Gprc5c becomes active when exposed to alkaline pH. No other GPCR studied does the same thing!

Metabolic studies on the knock-out mice that lack Gprc5c reveal mild acid build-up in the blood and loss of alkali in the urine. These observations are consistent with a role for this “orphan” in sensing alkali in the urine and promoting its reabsorbtion.

It’s fascinating to see systems we thought we had figured out get a new player. Of course, eventually this means altering my medical student lectures. I guess that’s the price of science!

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