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*The phosphorylated S or T residue is shown in red. All residues are given as their one-letter abbreviations (see Table 3-1). fX is any amino acid; B is any hydrophobic amino acid.

*The phosphorylated S or T residue is shown in red. All residues are given as their one-letter abbreviations (see Table 3-1). fX is any amino acid; B is any hydrophobic amino acid.

Binding of epinephrine (E) to b-adrenergic receptor triggers dissociation of Gsbg from Gsa (not shown).

Gsbg recruits bARK to the membrane, where it phosphorylates Ser residues at the carboxyl terminus of the receptor.

Binding of epinephrine (E) to b-adrenergic receptor triggers dissociation of Gsbg from Gsa (not shown).

Gsbg recruits bARK to the membrane, where it phosphorylates Ser residues at the carboxyl terminus of the receptor.

barr binds to the phosphorylated carboxyl-terminal domain of the receptor.

Receptor-arrestin complex enters the cell by endocytosis.

In endocytic vesicle, arrestin dissociates; receptor is dephosphorylated and returned to cell surface.

In endocytic vesicle, arrestin dissociates; receptor is dephosphorylated and returned to cell surface.

barr binds to the phosphorylated carboxyl-terminal domain of the receptor.

Receptor-arrestin complex enters the cell by endocytosis.

FIGURE 12-17 Desensitization of the ^-adrenergic receptor in the continued presence of epinephrine. This process is mediated by two proteins: ^-adrenergic protein kinase (^ARK) and ^-arrestin (^arr; arrestin 2).

^-adrenergic receptor kinase (^ARK) phosphory-lates Ser residues near the carboxyl terminus of the receptor. Normally located in the cytosol, ¡3ARK is drawn to the plasma membrane by its association with th Gspy subunits and is thus positioned to phosphorylate the receptor. The phosphorylation creates a binding site for the protein ^-arrestin (^arr), also called arrestin 2, and binding of ¡-arrestin effectively prevents interaction between the receptor and the G protein. The binding of ¡-arrestin also facilitates receptor sequestration, the removal of receptors from the plasma membrane by endocytosis into small intracellular vesicles. Receptors in the endocytic vesicles are dephosphorylated, then returned to the plasma membrane, completing the circuit and resensitizing the system to epinephrine. ¡-Adrenergic receptor kinase is a member of a family of G proteincoupled receptor kinases (GRKs), all of which phos-phorylate serpentine receptors on their carboxyl-terminal cytosolic domains and play roles similar to that of ¡ARK in desensitization and resensitization of their receptors. At least five different GRKs and four different arrestins are encoded in the human genome; each GRK is capable of desensitizing a subset of the serpentine receptors, and each arrestin can interact with many different types of phosphorylated receptors.

While preventing the signal from a serpentine receptor from reaching its associated G protein, arrestins can also initiate a second signaling cascade, by acting as scaffold proteins that bring together several protein kinases that function in a cascade. For example, the ¡-arrestin associated with the serpentine receptor for angiotensin, a potent regulator of blood pressure, binds the three protein kinases Raf-1, MEK1, and ERK (Fig. 12-18), serving as a scaffold that facilitates any signaling process, such as insulin signaling (Fig. 12-6), that requires these three protein kinases to interact. This is one of many known examples of cross-talk between systems triggered by different ligands (angiotensin and insulin, in this case).

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Diabetes 2

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