Homologous desensitization
Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration.[1] It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cellular effect of receptor activation is attenuated.[2]
Homologous desensitization is distinguished from
Homologous desensitization serves as a mechanism for
Mechanisms
For GPCRs generally, each mechanism of homologous desensitization begins with receptor phosphorylation by an associated G protein-coupled receptor kinase (GRK). GRKs selectively modify activated receptors such that no heterogeneous desensitization will occur. This phosphorylation then acts to recruit other proteins, such as arrestins, that participate in one or more of the following mechanisms.
Receptor uncoupling
Receptor uncoupling/phosphorylation is the most rapid form of desensitization that happens within a cell, as its effects are seen within seconds to minutes of agonist application.
The mechanism of homologous desensitization for the β2 receptor is as follows:
- Agonist binds and activates the receptor, which changes to an active conformational state.
- Beta adrenergic receptor kinase (βARK), a cytoplasmic kinase is activated and phosphorylates the C-terminus of the β2 receptor.
- This phosphorylation increases the affinity of β-arrestin for the receptor, resulting in uncoupling of the heterotrimeric G-protein from the receptor, producing desensitization.[citation needed]
Endocytosis
In contrast to receptor uncoupling, endocytosis can occur through multiple pathways. GPCR endocytosis has been shown to be either dependent or independent of arrestin activity, depending on the cell type used in the experiment; however, the former is more common. Furthermore, the same receptor expressed in two distinct cell types can be endocytosed through different mechanisms due to differences in GRK and arrestin expression: either through clathrin-coated vesicles or caveolae.[4] In general, receptor sequestration preferentially affects receptors that are both activated and phosphorylated, but the phosphorylation is not always a necessary component of endocytosis. After being sequestered, the affected receptors can either be degraded by lysosomes or reinserted into the plasma membrane, which is called receptor recycling.[5]
Post-translational modification also affects receptor endocytosis. For example, different