Gpcr proteins become desensitized in three general

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GPCR proteins become desensitized in three general ways. In any case, these processes are dependent on phosphorylation of GPCR by PKA, PKC, or a member of the family of GPCR kinases (GRK) which phosphorylate serines and threonines on GCPR proteins only after ligand binding (only the activated receptor allosterically activates the GRK): 1. Receptor sequestration: a ligand-bound receptor will be endocytosed into an endosome; the low pH of the endosome makes the ligand dissociate from the receptor. The receptor is then returned to the plasma membrane. 2. Receptor down-regulation: receptors are taken into the lysosome and degraded with the ligand. This often requires ubiquitination of the receptor. 3. Receptor inactivation: receptors become altered so that they can no longer interact with G-proteins. When GPCR proteins are phosphorylated by GRK, GPCR binds arrestin which both terminates the already-started G-protein signaling and recruits additional proteins to start the non-canonical signaling process that is independent of trimeric G-proteins. This binding of arrestin induces receptor-mediated endocytosis. CELL SIGNALING III RECEPTOR KINASES: Enzyme-coupled receptors are transmembrane receptor proteins with a ligand binding site on the extracellular domain. Rather than associating with G proteins, enzyme-
coupled receptors have an enzymatic cytosolic domain or associate directly with cytosolic enzymes. A receptor kinase is a type of enzyme-coupled receptor with a cytosolic domain that has enzymatic activity with an enzyme. Receptor tyrosine kinase regulates most aspects of cell survival, proliferation, metabolism, and differentiation. Thus, RTK mutations causes cancer. About 60 genes encoding RTK are found in humans. Many other genes encode another type of receptor kinase called serine/threonine kinase. Activated Tyrosine Kinases Phosphorylate Themselves: Ligand binding on the extracellular domain of RTK activates the tyrosine kinase domain on the cytosolic side. This leads to phosphorylation of tyrosine side chains on the cytosolic side of the receptor, creating phosphotyrosine docking sites for various intracellular proteins to relay the signal. Receptor dimerization is the most common way to activate receptor tyrosine kinases. Ligand binding causes two receptors to merge into a symmetrical dimer, increasing the kinase activity of the cytosolic domains. The cytosolic kinase domains phosphorylate one another within the kinase domain. This whole process is called transautophosphorylation. Some other receptor kinases are not activated by phosphorylation, but rather by conformational changes. For example, epidermal growth factor receptors (EGFRs) undergo cytosolic conformational changes when ligand binding occurs. Ligand binding causes dimerization; one cytosolic receptor end (the activator) pushes up against the other cytosolic receptor end (the receiver), causing an activating-conformational change of the receiver. The receiver then phosphorylates both cytosolic domains while the activator remains inactive.

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