Receptor Adaptation Mechanisms

Abstract Receptor adaptation mechanisms involve homeostatic regulation of the transmembrane receptors to maintain an optimal signalling response. Short‐term regulation of GPCRs is achieved when ligand‐/drug‐activated receptors become phosphorylated by GRKs, which reduces the G‐protein interaction. Phosphorylation of GPCRs also enhances the association with arrestins that block the G‐protein coupling, activate MAPK signalling and lead to internalisation of receptors. Internalised GPCRs may be recycled following dephosphorylation or degraded in the lysosome following ubiquitination. Prolonged drug treatments lead to desensitised receptors that require higher drug doses to achieve desirable responses, which may exacerbate adverse effects in nontarget tissues as the same receptor may be less desensitised. Long‐term regulation of receptors may be accomplished at the transcriptional and/or translational level to maintain receptor density. Key Concepts Receptors are temporally and spatially regulated in order to optimally transduce extracellular signals to modulate intracellular activities. There are three major classes of receptors including G‐protein‐coupled receptors, or GPCRs, ligand‐gated ion channels and growth factor receptors. Activated GPCRs elicit the canonical signalling by coupling to the heterotrimeric G‐proteins and may also activate other signalling pathways. Short‐term regulation of GPCRs is achieved first by GRK phosphorylation of the activated receptor, followed by the interaction with arrestin that blunts the G‐protein coupling (homologous desensitisation). Inactive GPCRs may be phosphorylated to reduce the G‐protein coupling following activation of a different GPCR that couples to the same G‐protein (heterologous desensitisation). Arrestins scaffold activated GPCRs to orchestrate the arrestin‐dependent signalling and to trigger receptor internalisation. Internalised GPCRs may be recycled following dephosphorylation and re‐inserted into the plasma membrane, or ubiquitinated and degraded in the lysosome. Biased ligands for GPCRs are developed to preferentially activate either the G‐protein or the arrestin‐dependent signalling pathway as each contributes to distinct physiological responses. GPCRs become desensitised following repeated pharmacological treatments, and desensitised GPCRs are less responsive to drugs/agonists. Long‐term regulation of receptors may be accomplished at the transcriptional and/or the translational levels.