Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain

Erdtmann-Vourliotis, Martina; Mayer, Péter; Ammon, Susanne; Riechert, Uta; Höllt, Volker

doi:10.1016/s0006-8993(01)03046-3

Cited by 86 publications

(52 citation statements)

References 39 publications

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“…The present study also suggests that GRK2 is likely to be the major isoform of GRKs that phosphorylates MOR and recruits ␤arr-2 in LC neurons (Erdtmann-Vourliotis et al, 2001). This interpretation is supported by the observation that MOR desensitization was ablated in neurons from w.t.…”

Section: Discussionsupporting

confidence: 65%

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dang

Napier²,

Christie³

2009

J. Neurosci.

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Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For manyGPCRs including the -opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of ␤-arrestins (␤arrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons. This study used whole-cell patch clamp recording of G-protein coupled inward-rectifying potassium (GIRK) currents to assay MOR function and identify mechanisms of acute MOR desensitization in locus ceruleus (LC) neurons. The rate and extent of MOR desensitization were unaffected by ␤arr-2 knock-out. Disruption of GRK2 function via inhibitory peptide introduced directly into neurons also failed to affect desensitization in wild type or ␤arr-2 knock-outs. Inhibition of ERK1/2 activation alone had little effect on acute desensitization. However, when both GRK2-␤arr-2 and ERK1/2 functions were disrupted simultaneously, desensitization of MOR was nearly abolished. Together, these results suggest that acute desensitization of MOR in native LC neurons is determined by at least two molecular pathways, one involving GRK2 and ␤arr-2, and a parallel pathway mediated by activated ERK1/2.

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Section: Discussionsupporting

confidence: 65%

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dang

Napier²,

Christie³

2009

J. Neurosci.

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“…CB 1 receptor desensitization occurred via a GRK3 and ␤-arrestin2-mediated mechanism in a heterologous expression model (Jin et al, 1999). There is evidence that GRK2, -5, and -6 are expressed in the striatum/BG, whereas GRK3 expression is low Erdtmann-Vourliotis et al, 2001). Both ␤-arrestin-1 and -2 are expressed in the striatum/BG, with higher levels of ␤-arrestin-1 reported in this region (Attramadal et al, 1992;Gurevich et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

McKinney

Cassidy²,

Collier³

et al. 2007

J Pharmacol Exp Ther

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Chronic treatment with ⌬ 9 -tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception, and hypothermia was produced by both ramping THC-dose paradigms. Administration of 10 mg/kg THC produced less tolerance development, the magnitude of which depended upon the particular behavior. Decreases in cannabinoid-mediated G-protein activation, which varied with treatment dose and region, were 35 S]GTP␥S binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [35 S]GTP␥S binding in the caudate-putamen, nucleus accumbens, and preoptic area occurred only after administration of 10 to 30 to 60 mg/kg THC, and no change was found in the globus pallidus or entopeduncular nucleus after any treatment. Changes in the CB 1 receptor B max values also varied by region, with hippocampus and cerebellum showing reductions after all treatments and striatum/globus pallidus showing effects only at higher dosing regimens. These results reveal that tolerance and CB 1 receptor adaptation exhibit similar dose-dependent development, and they are consistent with previous studies demonstrating less cannabinoid receptor adaptation in striatal circuits.Cannabinoids are used for their psychoactive effects and for therapeutic treatment of nausea/emesis and cachexia. Previous studies also suggest that cannabinoids may have clinical potential for the treatment of pain and degenerative disorders (Piomelli et al., 2000;van der Stelt and Di Marzo, 2003). Acute administration of cannabinoids produces antinociception, locomotor inhibition, hypothermia, and impairment of short-term memory (Howlett et al., 2002). ⌬ 9 -Tetrahydrocannabinol (THC) and other cannabinoids produce their psychoactive and behavioral effects via activation of CB 1 receptors in the central nervous system (CNS) (Ledent et al., 1999). Recent reports indicate that CB 2 and novel cannabinoid receptors might exist in the CNS (Mackie and Stella, 2006), but their role is unclear. CB 1 receptors are widely distributed in the brain where they exhibit a predominantly presynaptic location and modulate neurotransmitter release (Schlicker and Kathmann, 2001 [2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate; GP, globus pallidus; MPE, maximal possible effect; POA, preoptic a...

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“…Various kinases, including casein kinases (CKs) (Okochi et al, 2000), GRKs (Pronin et al, 2000), and Polo-like kinases (Inglis et al, 2009;Mbefo et al, 2010), phosphorylate ␣-syn at Ser129. We used GRK6 to generate Ser129-phosphorylated ␣-syn in the rat SNc for the following reasons: (1) GRK6 is known to be endogenously expressed in rat dopaminergic neurons (Fehr et al, 1997;Erdtmann-Vourliotis et al, 2001); (2) siRNA-mediated knockdown experiments show that endogenous GRK6 contributes to Ser129 phosphorylation of ␣-syn in HEK293 cells (Sakamoto et al, 2009); and (3) substituting arginine for lysine at position 215 (K215R) in GRK6 results in a catalytically inactive enzyme in cells (Willets et al, 2002). Here, we report that authentically Ser129-phosphorylated ␣-syn accelerates A53T ␣-syn-induced neurodegeneration, and that this effect can be abolished by inactivating the kinase.…”

Section: Introductionmentioning

confidence: 99%

Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

Sato¹,

Arawaka²,

Hara³

et al. 2011

J. Neurosci.

114

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Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the appearance of fibrillar aggregates of insoluble ␣-synuclein (␣-syn) called Lewy bodies (LBs). Approximately 90% of ␣-syn deposited in LBs is phosphorylated at serine 129 (Ser129). In contrast, only 4% of total ␣-syn is phosphorylated in normal brain, suggesting that accumulation of Ser129-phosphorylated ␣-syn is involved in the pathogenesis of PD. However, the role of Ser129 phosphorylation in ␣-syn neurotoxicity remains unclear. In this study, we coexpressed familial PD-linked A53T ␣-syn and G-protein-coupled receptor kinase 6 (GRK6) in the rat SN pars compacta using recombinant adeno-associated virus 2. Coexpression of these proteins yielded abundant Ser129-phosphorylated ␣-syn and significantly exacerbated degeneration of dopaminergic neurons when compared with coexpression of A53T ␣-syn and GFP. Immunohistochemical analysis revealed that Ser129-phosphorylated ␣-syn was preferentially distributed to swollen neurites. However, biochemical analysis showed that the increased expression of Ser129-phosphorylated ␣-syn did not promote accumulation of detergentinsoluble ␣-syn. Coexpression of catalytically inactive K215R mutant GRK6 failed to accelerate A53T ␣-syn-induced degeneration. Furthermore, introducing a phosphorylation-incompetent mutation, S129A, into A53T ␣-syn did not alter the pace of degeneration, even when GRK6 was coexpressed. Our study demonstrates that authentically Ser129-phosphorylated ␣-syn accelerates A53T ␣-syn neurotoxicity without the formation of detergent-insoluble ␣-syn, and suggests that the degenerative process could be constrained by inhibiting the kinase that phosphorylates ␣-syn at Ser129.

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Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain

Cited by 86 publications

References 39 publications

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

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Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain

Cited by 86 publications

References 39 publications

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol