Alternative splicing produces transcripts encoding four variants of mouse G-protein-coupled receptor kinase 6

A family of protein kinases, termed G-protein-coupled receptor kinases (GRK 1-6), is known to phosphorylate agonist-occupied G-protein-coupled receptor s, We have identified mRNAs encoding four distinct mouse GRK6 isoforms (mGR K6), designated mGRK6-A through mGRK6-D. Mouse GRK6-B and mGRK6-C diverge f rom the known human GRK6 (577 residues) at residue 560 and are 13 residues longer and 16 residues shorter, respectively, than human GRK6, while mGRK6- A very likely represents the mouse equivalent of human GRK6. Mouse GRK6-D i s identical to the other mGRK6 variants in the aminoterminal region, but co mprises only 59 of the 263 amino acids of the putative catalytical domain. As mGRK6-D retains the region involved in interacting with activated recept ors, but most likely lacks catalytic activity, this variant might represent a naturally occurring inhibitor of other GRKs. Analysis of the genomic org anization of mGRK6 gene revealed that the four mRNAs are generated by alter native RNA splicing from a single approximately 14.5-kb gene, made up of at least 17 exons and located on mouse chromosome 13, Similar to human GRK6, mGRK6-A contains three cysteine residues within its carboxyl-terminal regio n known to serve as substrates for palmitoylation. Mouse GRK6-B lacks these palmitoylation sites, but carries a basic carboxyl-terminus containing con sensus sequences for phosphorylation by protein kinases C and cAMP/cGMP-dep endent protein kinases. Mouse GRK6-C displays none of these motifs, Thus, m GRK6-A, mGRK6-B, and mGRK6-C are predicted to differ in terms of their regu lation by carboxyl-terminal posttranslational modification. Analysis of mRN A expression revealed that the four mGRK6 mRNAs are differentially expresse d in mouse tissues, suggesting that the four mGRK6 isoforms are involved in regulating tissue- or cell type-specific functions in vivo. (C) 1999 Acade mic Press.