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17.5.2 Receptor endocytosis

Endocytosis, also referred to asendosomal trafficking, is the process by which

lipids and proteins, including receptors, are taken into the cell from the plasma

membrane. It is a complex and dynamic process for which multiple pathways exist,

each involving characteristic scaffold and accessory proteins. The most important

pathways for membrane receptors are the clathrin-dependent and clathrin-independent

pathways.

The internalisation and trafficking of receptors has been most thoroughly investi-

gated using G-protein-coupled receptors, particularly the b 2 -adrenergic receptor.

Studies have revealed that the processes involve three stages:

• The recruitment of the receptors, normally with agonist bound to its orthosteric site
  (agonist-dependent internalisation) but in some cases in the absence of bound
  agonist (agonist-independent internalisation), to discrete endocytic sites such as
  rafts and caveolae in the membrane. In the case of the agonist-dependent route, the
  receptor is phosphorylated by a G-protein-coupled receptor kinase (GRK) and
  associated withb-arrestin prior to internalisation.


• The internalisation of the receptors to form anearly endosome,also referred to
  as asorting endosome.

Action A B C D E F G H I J

E13

E12

E7 E9 E11

E10

E6

E5

E1

Ligand I

Receptor I

Ligand II

Receptor II

Ligand III

E2a

E2b

Node 1

E3c

E3d

Node 2

E3a

E3b

E4c

Node 3

E4a

E4b

E8b

Node 4

E8a

Receptor IIlb

Node 5

Receptor IIla

d Network with critical nodes

Fig. 17.12Signalling pathways with critical nodes. Ligand binding to a receptor (I, II and III) activates the

receptor and in turn activates (full arrows) the linked effectors (numbers beside an effector E indicate distinct

proteins, the small letters indicate different isoforms of a given protein) leading to the transduction of one or

more actions (A to J) involving different nodes. The actions may result in the inhibition of the action of the

initiating ligand or of the receptor (blocked arrows). A ligand may also activate a second receptor but with less

intensity (dotted arrows). Activated effectors may alternatively either network with other effectors (arrows) or

inhibit other effectors (blocked arrows). (Adapted from Taniguchi, C. M., Emanuelli, B. and Kakn, C. R. (2006).

Critical nodes on signalling pathways: insights into insulin action.Nature Reviews Molecular Cell Biology,

7 , 85–96, by permission of Nature Publishing Group.)

704 Cell membrane receptors and cell signalling