Mechanisms of metabotropic glutamate receptor desensitization: role in the patterning of effector enzyme activation

doi:10.1016/S0197-0186(02)00073-6

Neurochemistry International

Volume 41, Issue 5, November 2002, Pages 319-326

https://doi.org/10.1016/S0197-0186(02)00073-6 Get rights and content

Abstract

Metabotropic glutamate receptors (mGluRs) constitute an unique subclass of G protein-coupled receptors (GPCRs). These receptors are activated by the excitatory amino acid glutamate and play an essential role in regulating neural development and plasticity. In the present review, we overview the current understanding regarding the molecular mechanisms involved in the desensitization and endocytosis of Group 1 mGluRs as well as the relative contribution of desensitization to the spatial-temporal patterning of glutamate receptor signaling. Similar to what has been reported previously for prototypic GPCRs, mGluRs desensitization is mediated by second messenger-dependent protein kinases and GPCR kinases (GRKs). However, it remains to be determined whether mGluRs phosphorylation by GRKs and β-arrestin binding are absolutely required for desensitization. Group 1 mGluRs endocytosis is both agonist-dependent and -independent. Agonist-dependent mGluRs internalization is mediated by a β-arrestin- and dynamin-dependent clathrin-coated vesicle dependent endocytic pathway. The activation of Group 1 mGluRs also results in oscillatory Gq protein-coupling leading to the cyclical activation of phospholipase Cβ thereby stimulating oscillations in both inositol 1,4,5-triphosphate formation and Ca²⁺ release from intracellular stores. These glutamate receptor-stimulated Ca²⁺ oscillations are translated into the synchronous activation of protein kinase C (PKC), which has led to the hypothesis that oscillatory mGluRs signaling involves the repetitive phosphorylation of mGluRs by PKC. However, recent experimental evidence suggests that oscillatory signaling is an intrinsic glutamate receptor property that is independent of feedback receptor phosphorylation by PKC. The challenge in the future will be to determine the structural determinants underlying mGluRs-mediated spatial-temporal signaling as well as to understand how complex signaling patterns can be interpreted by cells in both the developing and adult nervous systems.

Introduction

Metabotropic glutamate receptors (mGluRs) are members of the G protein-coupled receptor (GPCR) superfamily, the largest family of integral membrane receptor proteins. GPCRs are found in organisms ranging from slime mold and yeast to mammals and transduce the information provided by a wide variety of extracellular signals, including light, odor, taste, pheromones, hormones and neurotransmitters, to the interior of cells. GPCR signal transduction is achieved by the coupling of these receptors to a wide variety of effector systems through heterotrimeric guanine nucleotide binding proteins (G proteins; reviewed by Ferguson, 2001). Agonist-activated GPCRs function as guanine nucleotide exchange factors facilitating the exchange of GDP for GTP on the G protein α subunit, thus allowing the functional dissociation of the G_α and G_βγ subunits. The freely dissociated heterotrimeric G protein, G_α and G_βγ subunits then either positively or negatively regulate a variety of effector systems resulting in changes in intracellular second messenger levels and/or ion conductance.

Section snippets

The metabotropic glutamate receptor family

Glutamate is the major excitatory neurotransmitter in the central nervous system and is essential in the regulation of brain functions and neural cell development (Nakanishi, 1994, Conn and Pin, 1997). Glutamate mediates its actions through two distinct types of receptors, ionotropic glutamate receptors (iGluRs) and mGluRs. The iGluRs are cation-specific ion channels that mediate fast excitatory glutamate responses and are subdivided into AMPA/kainate and NMDA receptors (Nakanishi, 1994, Conn

Global paradigms of GPCR desensitization

Receptor desensitization fulfills an important physiological role by acting as the “thermostatic” or “feedback” mechanism limiting both acute and chronic over stimulation of GPCR signal transduction cascades. Receptor desensitization may be particularly relevant to the regulation of Group I mGluR activity, since the over stimulation of these receptors involves excitotoxicity leading to neuronal cell death associated with acute brain ischemia and neurotrauma (Nicoletti et al., 1996, Alessandri

Receptor phosphorylation

At least four families of protein kinases exhibit the capacity to phosphorylate GPCRs: (1) second messenger-dependent protein kinases (e.g. cAMP-dependent protein kinase, PKA and PKC); (2) casein kinase 1α; (3) tyrosine kinases; (4) the G protein-coupled receptor kinases (GRKs; Valiquette et al., 1990, Premont et al., 1995, Budd et al., 2000). GRKs specifically phosphorylate the agonist-activated form of GPCRs and thereby promote the binding of arresting proteins (arrestins) that further

GPCR endocytosis

An important aspect of GPCR activity and regulation is the internalization or endocytosis of agonist-activated receptors into the intracellular membrane compartments of the cell. GPCR internalization appears to be mediated by multiple distinct mechanisms, but the most common mechanism is the β-arrestin-dependent targeting of GPCRs for internalization via a clathrin-vesicle mediated pathway (Ferguson et al., 1996, Goodman et al., 1996, Zhang et al., 1996). The targeting of β-arrestin-bound

Metabotropic glutamate receptor desensitization

Recently, the mechanisms underlying Group 1 mGluR desensitization has been the subject of intensive investigation by several groups (Fig. 1). These studies reveal that mGluR desensitization may be mediated by both second messenger-dependent protein kinases and GRKs (Herrero et al., 1994, Desai et al., 1996, Gereau and Heinemann, 1998, Ciruela et al., 1999, Dale et al., 2000, Francesconi and Duvoisin, 2000, Sallese et al., 2000). However, these studies have often resulted in discordant results,

Role of second messenger-dependent protein kinases

The desensitization of Group 1 mGluRs is characterized as a decrease in phosphoinositide hydrolysis in response to repeated exposure to agonist. Group 1 mGluR desensitization has been described in neuronal cultures, hippocampal slices and heterologous cell culture systems (e.g. Schoepp and Johnson, 1988, Herrero et al., 1994, Desai et al., 1996). The first indication that second messenger-dependent protein kinases mediate the desensitization of Group 1 mGluRs came from studies utilizing both

Role of GRKs and arrestins

Recently, GRKs were also implicated in the desensitization of Group 1 mGluR activity (Dale et al., 2000, Sallese et al., 2000). Dale et al. (2000) found that GRK2 and GRK5 contributed to both the phosphorylation and desensitization of mGluR1a in HEK 293 cells. Although the expression of GRK4 and GRK6 resulted in mGluR1a phosphorylation (Dale and Ferguson, unpublished data), these kinases did not contribute to the desensitization of mGluR1a signaling (Dale et al., 2000). Moreover, the expression

Metabotropic glutamate receptor endocytosis

The internalization of mGluR1a appears to be mediated by both agonist-dependent and -independent mechanisms (Ciruela and McIlhinney, 1997, Doherty et al., 1999, Sallese et al., 2000, Dale et al., 2001a, Mundell et al., 2001). Unlike what is observed for many other GPCRs, substantial mGluR1a internalization is observed in the absence of agonist (Doherty et al., 1999, Dale et al., 2001a). This has been demonstrated both by the loss of cell surface receptors and the substantial localization of

Role of Group 1 mGluR desensitization in the patterning of effector enzyme activity

The activation of Group 1 mGluRs gives rise to repetitive base-line separated Ca²⁺-transients (oscillations; Kawabata et al., 1996, Nakahara et al., 1997, Kawabata et al., 1998, Codazzi et al., 2001, Dale et al., 2001b). These Ca²⁺ oscillations in response to mGluR activation are observed in immature neuronal cultures, developing neocortex, astrocytes, and heterologous cell cultures (Kawabata et al., 1996, Nakahara et al., 1997, Kawabata et al., 1998, Flint et al., 1999, Codazzi et al., 2001,

Conclusions

In conclusion, the temporal regulation of Ca²⁺ signaling represents a universal mechanism exploited by both excitable and non-excitable cells to regulate specific cellular responses. The Ca²⁺ oscillations in response to mGluR activation are observed in immature neuronal cultures and developing neocortex. Several studies have now determined that mGluR desensitization is regulated by the same mechanisms involved in the desensitization of more prototypic GPCRs. The activation of this important

Acknowledgements

S.S.G.F. is the recipient of a McDonald Salary Award and Great West/London Life Salary Award from the Heart and Stroke Foundation of Canada and a Premier’s Research Excellence Award from the Province of Ontario. A.V.B. is the recipient of a Canadian Hypertension Society/Canadian Institutes of Health Research (CIHR) fellowship. This work was supported by CIHR Grant MA-15506 to S.S.G.F.

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Mechanisms of metabotropic glutamate receptor desensitization: role in the patterning of effector enzyme activation

Abstract

Introduction

Section snippets

The metabotropic glutamate receptor family

Global paradigms of GPCR desensitization

Receptor phosphorylation

GPCR endocytosis

Metabotropic glutamate receptor desensitization

Role of second messenger-dependent protein kinases

Role of GRKs and arrestins

Metabotropic glutamate receptor endocytosis

Role of Group 1 mGluR desensitization in the patterning of effector enzyme activity

Conclusions

Acknowledgements

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J. Biol. Chem.

Progr. Neurobiol.

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FEBS Lett.

FEBS Lett.

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Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Neurosci.

Neuron

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Differential regulation of β2-adrenergic and angiotensin II type 1A receptor trafficking and resensitization: role of carboxyl-terminal domains

Mol. Endocrinol.

Functional desensitization of the isolated β-adrenergic receptor by the β-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48 kDa protein)

Proc. Natl. Acad. Sci. U.S.A.

Desensitization of metabotropic glutamate receptors in neuronal cultures

J. Neurochem.

Pharmacology and functions of metabotropic glutamate receptors

Ann. Rev. Pharmacol. Toxicol.

Differential regulation of β₂-adrenergic and angiotensin II type 1A receptor trafficking and resensitization: role of carboxyl-terminal domains