Abstract
Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mechanisms responsible for opioid-induced tolerance and addiction. The family of G protein receptor kinases (GRKs) play a pivotal role in such processes, mediating phosphorylation of residues at the C-tail of opioid receptors. Numerous strategies, such as phosphosite specific antibodies and mass spectrometry have allowed the detection of phosphorylated residues and the use of mutant knock-in mice have shed light on the role of GRK regulation in opioid receptor physiology. Here we review our current understanding on the role of GRKs in the actions of opioid receptors, with a particular focus on the MOR, the target of most commonly used opioid analgesics such as morphine or fentanyl.
Highlights
Our understanding of the function and regulation of opioid receptors (ORs) has improved dramatically since their identification in the seventies and subsequent cloning in the early 90 s
Cells 2020, 9, 2400 the mu-opioid receptor (MOR) subtype [14] and molecular changes at the MOR are known to contribute to the chronic effects of opioids, including changes in receptor-effector coupling and in receptor internalization, both of which are tightly controlled by receptor phosphorylation
After prolonged activation by an agonist, most G protein-coupled receptors (GPCRs) present at the plasma membrane undergo phosphorylation by G protein receptor kinases (GRKs) at specific serine and threonine residues located on intracellular loops or the C-terminus of the receptor
Summary
Our understanding of the function and regulation of opioid receptors (ORs) has improved dramatically since their identification in the seventies and subsequent cloning in the early 90 s. A fourth opioid receptor, that showed high homology to the recently identified MOR, DOR and KOR, was cloned in 1994 [6] but it failed to bind known endogenous and exogenous opioids. Cells 2020, 9, 2400 the MOR subtype [14] and molecular changes at the MOR are known to contribute to the chronic effects of opioids, including changes in receptor-effector coupling and in receptor internalization, both of which are tightly controlled by receptor phosphorylation. In this context, G protein receptor kinases (GRKs) are important modulators of opioid receptor function. We summarize our current understanding of the actions of GRKs on ORs, with a particular focus on the MOR and directing the reader to relevant literature for existing information on the other OR subtypes
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