Receptor Adaptation Mechanisms

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Receptor Adaptation Mechanisms

Bih‐Hwa Shieh, Vanderbilt University, Nashville, Tennessee, USA
Eugenia V Gurevich, Vanderbilt University, Nashville, Tennessee, USA
Vsevolod V Gurevich, Vanderbilt University, Nashville, Tennessee, USA

Published online: February 2020

DOI: 10.1002/9780470015902.a0000052.pub3

Full Article on Wiley Online Library

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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.

Keywords: desensitisation; downregulation; gene expression; pharmacology; G‐protein‐coupled receptors; β‐adrenergic receptor; rhodopsin; G‐protein‐coupled receptor kinase; arrestins; nicotinic acetylcholine receptor

Article Title:	Receptor Adaptation Mechanisms
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	Figure 1. A schematic representation of the visual cascade in the rod outer segment (ROS) of rod photoreceptors. ROS is the specialised signalling compartment consisting of numerous discs (grey box) where visual signalling takes place. Light activates rhodopsin in ROS by triggering isomerisation of 11‐cis (red squiggle) to all‐trans‐retinal (black squiggle). Activated rhodopsin (metarhodopsin II, shown as 7TM in red) interacts with the heterotrimeric transducin (G_t) and promotes the GDP‐GTP exchange (to the left). The GTP‐bound α‐subunit dissociates from the βγ subunit and switches on PDE. Activated PDE catalyses the hydrolysis of cGMP; a reduction of cGMP in photoreceptors shuts down cGMP‐gated channels in the plasma membrane, leading to hyperpolarisation of photoreceptors. cGMP is replenished by guanylate cyclase (GC). Rapid regulation of GPCRs signalling (that works with sub‐second kinetics in rod photoreceptors) was first discovered in the visual system (Kuhn and Dreyer, ; Kuhn et al., ). To terminate the visual signalling, metarhodopsin II is first phosphorylated by GRK1 (a.k.a. rhodopsin kinase, RK) (to the right). Phosphorylated metarhodopsin II interacts with arrestin‐1 (a.k.a. visual arrestin) that prevents its coupling to G_t, which is accomplished by a simple competition between arrestin‐1 and transducin (Krupnick et al., ; Wilden, ). Stable rhodopsin‐arrestin complexes may form that recruit AP‐1 in some pathophysiological conditions. The key components of the visual cascade and their subcellular distribution in disc membranes (green) or plasma membranes (blue) are indicated.
	Figure 2. A schematic representation of the intracellular events leading to homologous and heterologous desensitisation following activation of β₂‐ARs. Activated β₂‐ARs (red) couple to Gs leading to activation of AC (‘Canonical G‐protein‐mediated signalling’). Activated β₂‐ARs can be phosphorylated by GRK2 or GRK6 at its C‐terminus (Gurevich et al., ). This phosphorylation promotes an interaction with arrestin‐2 or arrestin‐3 (a.k.a. β‐arrestin1 and β‐arrestin2, respectively) that uncouples the receptor from G‐proteins, reducing G_s dependent signalling (homologous desensitisation). Arrestins also orchestrate internalisation of β₂‐ARs via clathrin‐mediated endocytosis (Goodman Jr. et al., ). Arrestin may serve as a signalling adaptor recruiting c‐Src (Luttrell et al., ) that transactivates EGFR by phosphorylation (reviewed in Gurevich and Gurevich, ; Peterson and Luttrell, ). Arrestins also may scaffold and activate MAPK (reviewed in Gurevich and Gurevich, ; Peterson and Luttrell, ). In heterologous desensitisation, β₂‐ARs can be phosphorylated by second messenger‐regulated protein kinases such as PKA; phosphorylation reduces the receptor's activity towards G_s and also switches the coupling of activated β₂‐ARs to G_i, the inhibitory G‐protein (Hausdorff et al., ). Phosphorylated residues in β₂‐ARs and EGFR are indicated by red stars. Adapted from Goodman Jr. et al., , Luttrell et al., , Gurevich and Gurevich, , Peterson and Luttrell, , Gurevich and Gurevich, , Hausdorff et al., .
	Figure 3. A schematic representation depicting regulation of nicotinic AChR expression in skeletal muscle by neuronal activity. In innervated muscles (a), acetylcholine (red dot) released from motor nerves activates nAChRs in the neuromuscular junction, resulting in an increase of intracellular Ca²⁺ leading to muscle contraction. The electrical activity associated with the muscle contraction also suppresses the transcription of the receptor subunit genes including α, β, δ and ϵ‐subunits in the neighbouring nuclei. Following denervation of the motor nerve (b), a lack of electrical activity up‐regulates the transcription of nAChR subunit genes, and the γ‐subunit gene is transcribed instead of the ϵ‐subunit resulting in the assembly of nAChR (α₂βγδ) with different channel kinetics and half‐life.