G protein-coupled receptor kinases (GRK) play an important role in phosphorylating and regulating the activity of G protein-coupled receptors. Complementary DNAs (cDNAs) that encode two novel members of the G protein-coupled receptor kinase (GRK) family are provided in the present invention. These cDNAs encode GRK5 (590 amino acids) and GRK6 (576 amino acids) which represent two new members of the GRK family that have distinct tissue distribution and substrate specificity. The availability of the cDNAs enables the generation of reagents to modulate the activity of endogenous kinases. These include dominant negative mutations and antisense oligonucleotides or stably transfected antisense constructs to block expression of the kinase to generate a cell with a reduced ability to desensitize to various agents. Expression of GRK5 and GRK6 also permits identification of specific inhibitors and activators of these two kinases. Such inhibitors and activators may be used therapeutically to either directly modulate the activity of a given receptor or by augmenting the ability of a given therapeutic agent to stimulate a given receptor.