GPCR dimers can exhibit novel signaling cascade, different from their monomers.
GPCR dimerization is a tricky area of drug discovery with many ambiguous details yet to be elucidated. This week, I came across an interesting paper in Nature Chemical biology on the signaling mechanisms of angiotensin 1 receptor (AT1-R) and alpha adrenergic 2c receptor (α2C-AR) following dimer formation. Using a series of BRET-based signaling assays, the authors identified that upon forced dimerization and dual activation of both receptors using native ligands, the heterodimer complex signals through Gs pathway, thereby leading to increase in cAMP! The authors conclude that prior knowledge of signaling pathways of monomers may not necessarily provide a complete picture of their signaling activity once they dimerize.
A couple of caveats that we need to keep in mind is that this data was obtained in a recombinant overexpression system (HEK293 cells) and brings up again the age-old question - Do these dimers really existing in native cells? and if they do, how relevant are they for human physiology? The other caveat is that this Gs signaling is only observed once the (larger) Gi signaling is blocked! So, not all dimers work through this alternate signaling pathway.
My condolences to all researchers who work in GPCR-dimerization, their work just got more complicated with needing to watch out for another ‘little’ proviso.
01/27 Bellot, M. et al. Dual agonist occupancy of AT1-R–α2C-AR heterodimers results in atypical Gs-PKA signaling. Nat Chem Biol advance online publication, (2015).