Divergent G-protein selectivity across melanopsins from mice and humans

Melanopsin is an opsin photopigment and light-activated G-protein-coupled receptor; it is expressed in photoreceptive retinal ganglion cells (mRGCs) and can be employed as an optogenetic tool. Mammalian melanopsins can signal via G(q/11) and G(i/o/t) heterotrimeric G proteins, but aspects of the mRGC light response appear incompatible with either mode of signalling. We use live-cell reporter assays in HEK293T cells to show that melanopsins from mice and humans can also signal via G(s). We subsequently show that this mode of signalling is substantially divergent between species. The two established structural isoforms of mouse melanopsin (which differ in the length of their C-terminal tail) both signalled strongly through all three G-protein classes (G(q/11), G(i/o) and G(s)), whereas human melanopsin showed weaker signalling through G(s). Our data identify G(s) as a new mode of signalling for mammalian melanopsins and reveal diversity in G-protein selectivity across mammalian melanopsins.