Bih‐Hwa Shieh, Vanderbilt University, Nashville, Tennessee, USA
Published online: January 2006
DOI: 10.1038/npg.els.0004077
Receptor adaptation mechanisms involve regulation of the number, sensitivity and subcellular localization of receptors that detect environmental cues and convert extracellular signals into a change of intracellular events.
Keywords: regulation of receptor desensitization; downregulation and gene expression; pharmacology; G protein‐coupled receptors; β‐adrenergic receptor; rhodopsin; G protein‐coupled receptor kinase; arrestins; nicotinic acetylcholine receptor
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Figure 1.
Schematic representation of intracellular events leading to homologous and heterologous desensitization following activation of β‐adrenergic receptor (β‐AR). β‐AR couples to Gs leading to activation of AC. Agonist activated β‐AR is phosphorylated by β‐ARK at its C‐terminus. Phosphorylated β‐AR interacts with β‐arrestin that prevents Gs activation by the receptor (homologous desensitization). β‐arrestin also acts as an adaptor protein to facilitate β‐AR internalization and to engage β‐AR to MAP kinase (MAPK) pathway. In heterologous desensitization, β‐AR is phosphorylated by protein kinases other than β‐ARK. For example PKA, which is activated by cAMP can modify β‐AR leading to diminished receptor activity towards Gs. Phosphorylated serine/threonine residues in β‐AR are labelled as orange dots. |
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Figure 2.
Rhodopsin mediates visual transduction in the rod outer segments (ROS). ROS are specialized compartments consisting of 2000 discs which are invaginated plasma membranes (lower panel). Shown in the upper panel is a section of ROS depicting signalling proteins and their distribution in disc or plasma membranes. Light activates rhodopsin by triggering isomerization of 11‐cis retinal to become all‐trans retinal in rhodopsin. Activated rhodopsin interacts with transducin (Gt), which turns on a cGMPphosphodiesterase (PDE). PDE catalyses the hydrolysis of cGMP leading to a reduced level of cGMP. Cyclic GMP is generated by guanylate cyclase (GC) and is responsible for opening of cGMP channels in the plasma membrane. Light leads to hyperpolarization of photoreceptors due to breakdown of cGMP resulting in closure of cGMP channels.To terminate the activity of activated rhodopsins, rhodopsin kinase modifies rhodopsins by phosphorylation. Phosphorylated rhodopsin interacts with arrestin that prevents its activity to activate Gt. Stable rhodopsin/arrestin complexes may be internalized for degradation of rhodopsins and to initiate apoptosis of photoreceptors. |
References
Alloway PG, Howard L and Dolph PJ (2000) The formation of stable rhodopsin–arrestin complexes induces apoptosis and photoreceptor cell degeneration. Neuron 28: 129–138.
Chen J, Makino CL, Peachey NS, Baylor DA and Simon MI (1995) Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH‐terminal truncation mutant. Science 267: 374–377.
Goldman D, Brenner HR and Heinemann S (1988) Acetylcholine receptor alpha‐, beta‐, gamma‐, and delta‐subunit mRNA levels are regulated by muscle activity. Neuron 1: 329–335.
Goodman OB Jr, Krupnick JG, Santini F et al. (1996) β‐arrestin acts as a clathrin adaptor in endocytosis of the β2‐adrenergic receptor. Nature 383: 447–450.
Jo SA, Zhu X, Marchionni MA and Burden SJ (1995) Neuregulins are concentrated at nerve–muscle synapses and activate ACh‐receptor gene expression. Nature 373: 158–161.
Kiselev A, Socolich M, Vinos J et al. (2000) A molecular pathway for light‐dependent photoreceptor apoptosis in Drosophila. Neuron 28: 139–152.
Kuhn H, Hall SW and Wilden U (1984) Light‐induced binding of 48‐kDa protein to photoreceptor membranes is highly enhanced by phosphorylation of rhodopsin. FEBS Letters 176: 473–478.
Luttrell LM, Ferguson SSG, Daaka Y et al. (1999) β‐arrestin‐dependent formation of β‐adrenergic receptor/src protein kinase complexes. Science 283: 655–661.
Xu J, Dodd RL, Makino CL et al. (1996) Prolonged photoresponses in transgenic mouse rods lacking arrestin. Nature 389: 505–509.
Further Reading
Duclert A and Changeux JP (1995) Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiological Reviews 75: 339–368.
Krupnick JG and Benovic JL (1998) The role of receptor kinases and arrestins in G protein‐coupled receptor regulation. Annual Review of Pharmacology and Toxicology 38: 289–319.
Luttrell LM and Lefkowitz RL (2002) The role of β‐arrestins in the termination and transduction of G‐protein‐coupled receptor signals. Journal of Cell Science 115: 455–465.
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