The GRK4 subfamily of G protein-coupled receptor kinases - Alternative splicing, gene organization, and sequence conservation

G protein-coupled receptor kinases (GRKs) desensitize G protein-coupled rec eptors by phosphorylating activated receptors. The six known GRKs have been classified into three subfamilies based on sequence and functional similar ities. Examination of the mouse GRK4 subfamily (GRKs 4, 5, and 6) suggests that mouse GRK4 is not alternatively spliced in a manner analogous to human or rat GRK4, whereas GRK6 undergoes extensive alternative splicing to gene rate three variants with distinct carboxyl termini. Characterization of the mouse GRK 5 and 6 genes reveals that all members of the GRK4 subfamily sha re an identical gene structure, in which 15 introns interrupt the coding se quence at equivalent positions in all three genes. Surprisingly, none of th e three GRK subgroups (GRK1, GRK2/3, and GRK4/5/6) shares even a single int ron in common, indicating that these three subfamilies are distinct gene li neages that have been maintained since their divergence over 1 billion year s ago. Comparison of the amino acid sequences of GRKs from various mammalia n species indicates that GRK2, GRK5, and GRK6 exhibit a remarkably high deg ree of sequence conservation, whereas GRK1 and particularly GRK4 have accum ulated amino acid changes at extremely rapid rates over the past 100 millio n years. The divergence of individual GRKs at vastly different rates reveal s that strikingly different evolutionary pressures apply to the function of the individual GRKs.