Tag Archives: PKA RIalpha

The cell is not a bag of water

We have over 800 G protein coupled receptors (GPCRs).  We have not found 800 distinct intracellular messengers (such cyclic adenosine monophosphate — aka CAMP).  A single cell can express up to 100 GPCRS — Mol. Pharm. vol. 88 pp. 181 – 187 ’15.  Some of them raise CAMP levels, others decrease it.  CAMP is supposed to diffuse freely within the cell.  If so, different GPCRs which change cellular CAMP levels to the same extent they should produce identical effects. But they don’t.

One example — Isuprel stimulation of beta adrenergic GPCRs increases cardiac contractile force and activates glycogen metabolism.  Prostaglandin E1 (PGE1) GPCR causes the same CAMP increase without this effect.

A recent fascinating paper may explain why [ Cell vol. 185 pp. 1130 – 1142 ’22 ]  The authors had previously done work showing that under basal conditions CAMP is mostly bound to a protein (regulatory protein kinase A subunit — aka PKA RIalpha ) leading to very low concentrations of free CAMP.

So free diffusion occurs only if CAMP levels are elevated well above the number of binding sites for it.

As usual, to get new interesting results, new technology had to be used.  A biosensor for CAMP based on Forster Resonance Energy Transfer aka FRET —  https://en.wikipedia.org/wiki/Förster_resonance_energy_transfer, was added to two different GPCRs — one for the Glucagon Like Peptide 1 (GLP1) and the other for the beta2 adrenergic receptor.

Even better, they fused the biosensor to the GPCRs using rulerlike  spacers each 300 Angstroms (30 nanoMeters) long.  So they could measure CAMP levels at 30 and 60 nanoMeters from the GPCR.  Levels were highest close to the receptor, but even at 30 and 60 nanoMeters away they were higher than the levels in the cytoplasm away from the cell membrane.  So this is pretty good evidence for what the authors call RAINs (Receptor Associated Independent camp Domains — God they love acronyms don’t they?).

Similar localized responses were seen with the beta2 adrenergic receptors, suggesting that RAINs might be a general phenomenon of GPCRs — but a lot more work is needed.

Even more interesting was the fact that there was no crosstalk between the RAINS of GLP1R and the beta2 adrenergic receptor.  Stimulation of one GPCR changed only the RAIN associated with it and didn’t travel to other RAINs

So the cell with its GPCRs resembles a neuron with its synapses on dendritic spines, where processing at each synapse remains fairly local before the neuron cell body integrates all of them.  It’s like Las Vegas — what happens at GPCR1 (synapse1) stays in GPCR1 (synapse1).  Well not quite, but you get the idea.