Abstract
Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.
Highlights
Activation-dependent phosphorylation of rhodopsin was discovered in the early 1970s [1,2], long before it became clear that rhodopsin belongs to the family of G proteincoupled receptors (GPCRs)
It was shown that cAMPactivated protein kinase A (PKA) phosphorylates β2-adrenergic receptor (β2AR) on the third cytoplasmic loop, whereas the eight GPCR kinase (GRK) phosphorylation sites are localized in the receptor C-terminus
While this study suggested that serines in the rhodopsin C-terminus are phosphorylated first, a recent study suggested that phosphothreonines are more important for arrestin-1 binding in photoreceptors [103]
Summary
Activation-dependent phosphorylation of rhodopsin was discovered in the early 1970s [1,2], long before it became clear that rhodopsin belongs to the family of G proteincoupled receptors (GPCRs). The behavior of every GPCR with regard to GRK-dependent phosphorylation and its effects on G protein coupling, subsequent arrestin binding, and arrestin-mediated signaling is different and has to be studied as such, instead of relying on information obtained with “model” receptors. This is important for clinically relevant GPCRs, which are targeted by numerous therapeutically important drugs
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