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known as NSF. Chimeras of the receptor lacking the PDZ domain are directed to the

degradative pathway. GPCRs sorted for recycling are first dephosphorylated by an

endosome-associated phosphatase and recycled back to the membrane via the Golgi

complex. In the case of receptors directed to degradation, the sorting signal directs the

receptors to so-calledlate endosomesthat have a multivesicular appearance referred

to asmultivesicular bodies(MVBs) that contain a number of protein complexes

known asendosomal sorting complex required for transport(ESCRT-I-III) which

promote the fusion of the endosome with a lysosome. The resulting decrease in pH

within the vesicle to 5.3 facilitates the downregulation of the receptor by proteolysis.

Ligand

molecules

Unoccupied receptors

Membrane

(1) Receptor-

ligand

binding Clathrin-coated

pit

(6) Newly synthesised

receptors secreted into

membrane by exocytosis

(2) Endocytosis

(4) Receptor recycling

pathway directed

by receptor PDZ

recyclingClathrin domain and EBP50

Golgi

complex

(3) Clathrin

network

depolymerised

via hsp70

Coated vesicle

(early endosome) (5) Fusion with a lysosome and

receptor degradation via proteosomes

directed by ubiquitin (downregulation)

Ub

Ub

Uncoated vesicle

(endosome)

Degradation pathway directed

by nexin1

Receptor
phosphorylation
by GRK and assembly
into coated pits by
β-arrestin and AP-2

β-Arrestin

P

P

P

Fig. 17.13Pathway of agonist-dependent G-protein-coupled receptor internalisation and endocytic sorting.

(1) Occupied receptors are phosphorylated (P) by a G-protein-coupled receptor kinase (GRK) leading to the

recruitment ofb-arrestins. Arrestins serve as adaptor proteins by linking phosphorylated receptors to

components of the transport machinery such as clathrin and adaptor protein AP-2 and their recruitment to

clathrin-coated pits. (2) The coated pit ‘buds’ into the cytoplasm aided by the clathrin which forms a network

leading to the formation of an endosome. Note that the cytoplasmic domain of the receptor remains exposed to

the cytoplasm following endocytosis. (3) The clathrin network is depolymerised and the clathrin recycled to the

inner membrane. (4) The receptors are dephosphorylated and as a result of the interaction of EBP50 with a PDZ

domain on the receptor, traffic back to the cell surface resulting in functional resensitisation. Alternatively,

(5) dephosphorylated receptors are tagged with ubiquitin (Ub) and enter the degradation pathway. Here they

interact with nexin1 and ESCRTs which promote the fusion of the endosome with a lysosome and the

degradation of the receptor by a number of proteasomes – a process known as downregulation. (6) The Golgi

complex secretes newly synthesised receptor molecules to the outer membrane surface by exocytosis. The

balance between receptor cycling, receptor degradation and receptor synthesis and exocytosis determines the

number of functionally active receptors on the membrane surface at any time.

706 Cell membrane receptors and cell signalling