GPCR Signaling: β-arrestins Kiss and Remember

Abstract

β-arrestin-dependent activation of the ERK MAP kinase downstream of GPCRs typically originates from internalized receptor-β-arrestin-ERK complexes. A new study now reports that β-arrestin 2 is sufficiently 'primed' after 'kissing' the β1-adrenergic receptor to initiate ERK activation even in the absence of formation of the receptor-β-arrestin-ERK complex and receptor internalization.

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

“…It has been suggested that, like G proteins, arrestin might be able to dissociate from active β 1 -AR while still retaining an activated signaling conformation, a "memory effect" (16,18). From our observations with the M 1 R, we can say that the recorded arrestin conformational change in the unliganded transient complex with receptor reverses very quickly after arrestin unbinds with no memory effect after transient binding.…”

“…Electron microscope images of arrestin-receptor complexes together with modeling suggest that β-arrestin binds in two different modes, called transient binding and stable binding, to chimeric β 2 adrenergic receptors (β 2 -AR) containing the C terminus of vasopressin type 2 receptors (3). X-ray crystal structures of rhodopsin-arrestin complexes also support such a concept (4).From these observations, a common inference is that ERK activity is up-regulated while scaffolded on arrestin-GPCR complexes.An interesting alternative mechanism has been suggested recently, namely a briefly persistent conformational change of arrestin that allows it to continue to signal to ERK after dissociation from GPCRs (17)-a "memory effect" (16,18). We studied the M 1 muscarinic acetylcholine receptor (M 1 R), which couples to both G q -and arrestin-dependent pathways, including ERK activation (19)(20)(21)(22), and found strong evidence for two binding modes of arrestin to receptors that led to contrasting downstream signals.…”

“…An interesting alternative mechanism has been suggested recently, namely a briefly persistent conformational change of arrestin that allows it to continue to signal to ERK after dissociation from GPCRs (17)-a "memory effect" (16,18). We studied the M 1 muscarinic acetylcholine receptor (M 1 R), which couples to both G q -and arrestin-dependent pathways, including ERK activation (19)(20)(21)(22), and found strong evidence for two binding modes of arrestin to receptors that led to contrasting downstream signals.…”

“…For example, β-arrestin has binding sites for cRaf (MAPK kinase kinase), MEK (MAPK kinase), and ERK (MAPK) that mediate a signaling cascade for cell proliferation, cell migration, and actin dynamics after GPCR activation (10)(11)(12)(13). Conventionally, MEK-dependent ERK signaling is described as involving GPCR-arrestin complexes on intracellular compartments such as endosomal vesicles (10,(14)(15)(16). However, whether similar complexes at the plasma membrane might trigger ERK signaling remains unknown.…”

Functional competence of a partially engaged GPCR–β-arrestin complex

“…This observation indicates that both, class A and B receptors are capable of undergoing endocytosis and triggering ERK activation when engaged with βarrs only through the phosphorylated carboxyl terminus. Along similar lines, a recent investigation has documented that βarr2 can mediate ERK activation downstream of β 1 AR despite a very transient interaction and dissociation from the receptor5152. Going forward, it would be interesting to test additional receptor systems to evaluate the generality of these observations in a broader context.…”