Agonist‐selective mechanisms of GPCR desensitization

Abstract

The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by a family of kinases called the G protein-coupled receptor kinases (GRKs). The GRK-phosphorylated receptor then acts as a substrate for the binding of a family of proteins called arrestins, which uncouple the receptor and G protein so desensitizing the agonist-induced response. Other kinases, principally the second messenger-dependent protein kinases, are also known to play a role in the desensitization of many GPCR responses. It is now clear that there are subtle and complex interactions between GRKs and second messengerdependent protein kinases in the regulation of GPCR function. Functional selectivity describes the ability of agonists to stabilize different active conformations of the same GPCR. With regard to desensitization, distinct agonist-activated conformations of a GPCR could undergo different molecular mechanisms of desensitization. An example of this is the m opioid receptor (MOPr), where the agonists morphine and [D-Ala 2 ,N-MePhe 4 ,Gly-ol 5 ]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)-or GRK-dependent, respectively. This can be best explained by supposing that these two agonists stabilize distinct conformations of the MOPr, which are nevertheless able to couple to the relevant G-proteins and produce similar responses, yet are sufficiently different to trigger different regulatory processes. There is evidence that other GPCRs also undergo agonist-selective desensitization, but the full therapeutic consequences of this phenomenon await further detailed study.

Optical measurement of mGluR1 conformational changes reveals fast activation, slow deactivation, and sensitization

“…We investigated whether long-lasting agonist application could induce desensitization as reported for native GPCRs (27). However, we did not observe desensitization of the FRET response even with glutamate concentration as high as 1 mM and glutamate exposure times up to tens of minutes.…”

Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

“…Desensitization due to receptor internalization is a common feature of G-protein coupled receptors. 37 In the classic desensitization model, repeated exposure to the ligand initiates receptor desensitization by phosphorylating the receptor, thus preventing the coupling of G-protein and a loss of response (i.e., tachyphylaxis) to receptor activation. 38 Recent studies have reported tachyphylaxis in regards to the permeability response to LPA.…”

G protein inhibition of CaV2 calcium channels

“…Desensitization is complex and for some receptors (e.g., the μ-opioid receptor) can be mediated by distinct signaling pathways depending upon the identity of the bound agonist. 30 Phosphorylation by PKA, PKC or G protein coupled receptor kinases (GRKs) is involved and can result in uncoupling of the receptor from the downstream G proteins. Endocytic removal of the GPCR from the plasma membrane can also occur: GRKs, recruited by Gβγ, phosphorylate the span the plasma membrane.…”