Endocytosis sequestration

Figure 123 Molecular mechanism of (homologous) GPCR regulation: desensitization and internalization. Reproduced by permission of the Company of Biologists, Journal of Cell Science, 115, Luttrell, L. M. and Lefkowitz, R. J., The role of beta-arrestins in the termination and transduction of G protein-coupled receptor signals, Fig. 1, 455-465, Copyright (2002).

signal). In this respect, it was noted in several cases that mutant, C-terminally truncated receptors couple to G proteins with improved efficacy. A possible explanation for this hypersensitivity is due to the removal of threonine and/or serine residues, which are involved in mediating GPCR desensitization by serving as substrates for GRKs.

Finally, it should be noted that the nature of the cellular host in recombinant systems strongly influences the ability of the transfected receptors to desensitize. This has been well documented for the P3-adrenergic receptor (which does not serve as substrate for GRK and does not bind P-arrestins):

• The human p3-adrenergic receptor desensitizes to isoproterenol in SK-N-MC and HEK293 cells, but not in CHO cells.

• The rat p3-adrenergic receptor desensitizes in HEK293 cells, but not in rat adipocytes.

Interestingly, p-arrestin binding does not necessarily represent 'the end' of a GPCR. Instead, it may even endow the receptor with a 'new life'. This is because p-arrestins have the ability to bind to several proteins, which play a role either in endocytosis or in signalling (Figure 122). Regions involved in receptor or membrane recognition are shown in blue, those involved in controlling p-arrestin interaction with the endocytotic machinery are shown in red, while proposed interactions between p-arrestins and signalling proteins are shown in green:

• The A functional domain is responsible for recognition of activated GPCRs and the B domain is responsible for secondary receptor recognition. Both domains are separated by a phosphate sensor domain (P).

• The regulatory R2 domain contains the primary site of phosphorylation as well as the LIEF binding motif for clathrin and the RXR binding motif for the p2-adaptin subunit of the heterotetrameric AP-2 adaptor complex. (This complex is involved in the initiation of clathrin-coated pit formation.)

• Binding to the c-Src-SH3 domain occurs to one or more PXXP motifs within the A domain of p-arrestin 1.

• Binding to MAP kinases occurs to a recognition sequence, RRSLHL, within the B domain of p-arrestin 2.

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