User:Swalk22/sandbox

Homologous Desensitization (intro from article)

Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration. It is the process whereby, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the biological effect of receptor activation is attenuated. Homologous desensitization should not be confused with heterologous desensitisation, which is a different process whereby receptor stimulation results in desensitization of other, usually non active, receptors on the same cell. They are sometimes denoted as agonist-dependent and agonist-independent desensitization respectively. While heterologous desensitization occurs rapidly at low concentration, homologous desensization shows a dose dependent response and usually begins at significantly higher concentrations than its counterpart.

Homologous desensitization serves as a mechanism for Tachyphylaxis and helps organisms to maintain homeostasis. The process of homologous desensitization has been extensively studied utilizing G protein–coupled receptors (GPCRs), thus, they are the focus of this article. While the different mechanisms for desensitization are still being characterized, there are currently 3 known mechanisms: uncoupling of receptors to associated G proteins, endocytosis, and degredatation/downregulation of receptor expression. The degredation and downregulation of receptors is often also associated with drug tolerance since it has a longer onset, from hours to days. It has been shown that these mechanisms can happen independent of one another, but that they usually do influence each other in some way. This has lead to an issue in characterizing each mechanism individually, since the mechanisms might be very different in vivo from the in vitro experiments. In addition to the in vivo complications, studies show that the same receptor expressed in different cell types will be desensitized by different mechanisms.

Mechanisms

In general for GPCRs, each mechanism for homologous desensitization will begin by receptor phosphorylation by an associated G protein-coupled receptor kinase (GRK). GRKs selectively stimulate activated receptors such that no heterogeneous desensitization comes from this pathway. This phosphorylation then acts to recruit other proteins, such as Arrestins, that help achieve one or more of the following mechanisms.

Receptor Uncoupling (maybe call phosphorylation... I just feel its miselading. Thoughts?)

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. Since the ß₂ adrenergic receptor was the first to have its desensitization studied and characterized, it will serve as the example for this discussion. The mechanism of desensitization involves the action of a specific GRK, denoted ßARK, and also ß-arrestins. The ß-arrestins show high affinity for receptors that are both phosphorylated and activated, but are still able to bind non-phosphorylated receptors with a lower affinity. Additionally, ß-arrestins are better at inactivating ßARK phosphorylated receptors rather than PKA phosphorylated receptors, which suggests that the arrestins preferentially mediate homologous desensitization.

Keep what was previously there, change the mechanism to a mechanism.

Endocytosis/Sequestration (I could add tyrosine kinase receptors here, which have a more concrete mechanism)

In contrast to the mechanism presented above, endocytosis does not happen in one clear pathway. GCPR endocytosis has 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 in two mechanism due to differences in GRK and arrestin expression: through Clathrin-coated vesicles and caveolae. In general, receptor sequestration preferentially affects receptors that are both activated and phosphorylated, but the phosphorylation is not always a necessary component to endocytosis. After being sequestered, the affected receptors can either be degraded by lysosomes or reinserted into the plasma membrane, which is called recycling.

Post-translational modification also affect receptor endocytosis. For example, different glycosylations on the exterior N terminus of dopmine receptors D2 and D3 were associated with specific endocytic pathways. Additionally, palmitoylation, which primarily helps with receptor localization to the membrane, can also affect endocytosis. It is required for the endcytosis of TRH and D3 receptors, it is inhibitory for LH and V_1A receptors, and it has shown to have no affect on adrenergic receptors (specifically ß2 and α₁).

See Also

• Tachyphylaxis
• drug tolerance
• G protein–coupled receptor
• G protein-coupled receptor kinase
• Arrestin
• Endocytosis

Notes about additional references

1. "G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins"
   • phosphorylation most rapid. Used in neurons especially at synapses.
   • Once again, some receptors neeed GRK's and others don't. olfactory and visual are sensitive to GRK mutations.
   • GRKs normally receive modifications, upon stimulation, that signal translocation to the cell membrane. (for GRK 1-3, GRKs 4-6 are usually close to membrane w/o agonist). (I could choose to make a table w/ the GRK's but that should go on the GRK page...)
     • Arrestins associate after GRKs 1-3, but GRKs 4-6 still unknown (at this time since old review paper). Make sure to provide a link to arrestins! (lots of info on that pg)
   • Although GRK's are able to phosphorylae many sites, thought that only the initial is necessary for the signal.
   • Unkown how arrestins associate/move towards the membrane. Arrestins prefer activated, but also bind phosphorylated receptors, even if not active.
     • Divergent sequences at N and C termini. C terminal domain thought to give specificity.
   • endocytosis happens via clathrin and caveolae.
2. "Regulatory Mechanisms that modulate signalling by G-protein Coupled receptors"
   • have 3 intracellular loops + C terminal tail.
   • ßARKs highly expressed in post-synaptic neurons. suggests importance of function, physiologically.
   • Arrestins can bind non-phosphorylated channels, but with lower affinity.
   • Article also talks about non GPCRs, specifically receptors that are cleaved when they're activated. They are endocytosed and cannot be recycled (ofc)
     • mentions specific domains for endocytosis. I don't think this is relevant for the wiki article
   • arrestins usually act w/ dynamin to form the clathrin mediated pits for endocytosis. Although overexpression can rescue internalization in dynamin- systems.
   • down regulation - long term. could maybe write another section about this.

References for possible topics

1. "Rate of Homologous desensitization and Internalization of the GLP-1 Receptor."
2. "Desensitization of the human 5-HT4 receptor in isolated atria of transgenic mice"
3. "Multifactorial Regulation of G Protein-Coupled Receptor Endocytosis"
4. "Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling" - actually a reveiw article about the subject
5. For powerpointpresentation (this has the figure I used).