The Origins of GPCRs.

G protein-coupled receptors (GPCRs) are present in all kingdoms of life. GPCRs are the largest family of signaling proteins in animals, including humans. Numerous lines of indirect evidence suggest that eukaryotic light-sensitive rhodopsins (usually called type II), as well as other structurally similar non-visual GPCRs, trace their origins from prokaryotic rhodopsins (type I), possibly via receptors in unicellular eukaryotes that have a similar transmembrane core, even though existing sequence analysis software cannot detect homology. Bacterial and archaeal rhodopsins share the same overall design with eukaryotic GPCRs: a flexible core consisting of seven transmembrane α-helices with an extracellular N-terminus, an intracellular C-terminus, and three loops on each side of the membrane. Both families include many hundreds of members and apparently have expanded for billions of years, which makes the results of direct comparisons of the sequence and structure of these groups of proteins inconclusive. The distribution of residues with aromatic and ionizable side chains in prokaryotic rhodopsins and eukaryotic GPCRs was found to be similar. Established similarities suggest that shared origins are possible but do not unambiguously prove this hypothesis.