Arrestins

New findings demonstrate that P-arrestins also act as adaptors that directly link GPCRs to proteins involved with endocytosis (Fig. 7.1a). Consistent with this idea, P-arrestin binding

Endocytosis

^ [mkk MAPK Signaling

Endocytosis

Signal 3?

Signal 1

Signal 3?

Signal 1

CGRP

Adrenomedullin

Amylin n

Signals

Signals

Adrenomedullin

Amylin n

N-type Ca++ Channels M-type K+ channels

N-type Ca++ Channels M-type K+ channels

Cytoskeleton

Fig. 7.1 Proteins that regulate GPCR functions

Cytoskeleton

Fig. 7.1 Proteins that regulate GPCR functions to phosphorylated receptors is required for receptors to be targeted to internalized vesicles (Ferguson et al. 1996). Other studies demonstrate that ß-arrestins bind the heavy chain of clathrin by way of a specific C-terminal binding motif (L-I-E-L/F) (Goodman et al. 1996, 1997) depending on the phosphorylation state of ß-arrestin (Lin et al. 1997). ß-arrestins also directly link GPCRs to other proteins involved in formation of endocytotic vesicles. Adapter protein-2 (AP-2) binds clathrin and is essential for GPCR targeting to coated pits and endo-cytic vesicles (Laporte etal. 1999). ß-arrestins bind directly to AP-2, and complex formation between GPCRs, ß-arrestin, AP-2 and clathrin are essential for targeting GPCRs to clathrin-coated pits (Laporte et al. 2000). Recent studies also indicate that certain GPCRs interact directly with the N-ethyl maleimide fusion protein (NSF), that is, an ATPase involved with intracellular membrane trafficking (McDonald et al. 1999). Taken together, these observations indicate that ß-arrestins act as adaptors that directly link GPCRs to proteins important for endocytosis. Emerging models propose that, in certain cases, receptor/ß-arrestin complex formation and interaction with clathrin and AP-2 is essential for targeted GPCR localization and intracellular trafficking (Miller et al. 2000).

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