CRF receptors are widely regulated by arrestins and GRK. The receptor contains seven putative sites of GRK phosphorylation on the C-terminal domain that may be involved in β-arrestin recruitment. Among the different GRK, GRK3 and GRK6 translocate to the membrane after CRF stimulation in a HEK cell model and contribute to CRF1 receptor desensitization. Reducing GRK3 expression reduces CRF1 receptor desensitization, while GRK3 overexpression in HEK cells promotes a more rapid desensitization. Contrary to CRF2, the extreme C-terminus of the CRF1 receptor contains a type 1 PDZ domain. Considering that PDZ domains can be phosphorylated by GRK or bind to PSD-95 and other modulatory proteins, its presence introduces another potential element of response modulation.
