Proteins regulating receptor trafficking and clustering

The vast majority of GPCRs can undergo agonist-induced internalization into an endosomal compartment with or without bound ligand. This can occur very rapidly (e.g. 12% of muscarinic acetylcholine receptors in neuroblastoma cells are removed from the cell surface within a minute of agonist activation) or over a more prolonged time period. Once the agonist is removed from the GPCR the receptor can be recycled back to the plasma membrane. Classically, when the rate of internalization and recycling are at equilibrium 5% of receptors are turned over every minute. These dynamic changes in receptor expression at the cell surface provide a mechanism for processes such as: (i) short-term desensitization, (ii) initiation to long-term desensitization, (iii) retrograde signalling whereby internalized agonist receptor complex acts as a signalling mechanism transported down axons, (iv) dephosphorylation, and (v) morphological change. The mechanism by which receptors are internalized is via clathrin-coated pits and often involves cytoskeletal elements. Smooth pits have also been implicated for certain receptors, such as CCK (Chapter 14), although the relative importance of this mechanism versus clathrin coated pits is unclear. The structural requirements for internalization vary from receptor to receptor. Thus for |32 adrenoreceptors Tyr326 at the junction of the seventh TM domain and the C-terminal sequence is thought to be important but the analogous aromatic amino acid forming part of an 'NPXY' domain in GRP and angiotensin receptors is not implicated in this process. In general mutations in the second and third intracellular loops and C-terminal tail have been implicated in internalization with many producing subtle changes in the rates of internalization versus recycling rather than a clear cut on off modulation of one or both processes. Certainly, it is quite likely that cytoskeletal interactions, agonist binding kinetics and differential kinase phosphorylation can markedly affect internalization. Below is a description of some of the protein interactions that have a bearing on receptor clustering and trafficking:

0 0

Post a comment