Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain

Ferrari, Luiz F.; Bogen, Oliver; Alessandri‐Haber, Nicole; Levine, Emma; Gear, Robert W.; Levine, Jon D.

doi:10.1016/j.neuroscience.2012.07.004

Cited by 49 publications

(50 citation statements)

References 52 publications

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“…Earlier studies by us and others have shown that Epac1 protein levels in the DRG are increased in the CFA model of chronic inflammatory pain, whereas GRK2 levels are decreased (16,17,(30)(31)(32). In addition, we presented evidence that Epac1-dependent pain signaling is inhibited by GRK2, but the mechanism remained to be determined (17).…”

Section: Discussionmentioning

confidence: 47%

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Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

Singhmar

Huo

Eijkelkamp

et al. 2016

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

107

114

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cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1 −/− mice are protected against inflammatory hyperalgesia in the complete Freund's adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1 −/− , mice. Using sensory neuronspecific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain.

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Section: Discussionmentioning

confidence: 47%

“…***P < 0.001; ****P < 0.0001. 32 P incorporation in WT-Epac1 and Epac1-S108A incubated with purified recombinant GRK2 (50 nM). (E) Rap1 activation in N2A and N2A-GRK2 (NG) cells transfected with WT-Epac1 (WT), Epac1-S108A (S108A), or Epac1-S108E (S108E) treated with 8-pCPT.…”

Section: Phosphorylation Of Epac1 At Ser-108 Inhibits Rap1 Activation Bymentioning

confidence: 99%

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

Singhmar

Huo

Eijkelkamp

et al. 2016

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

107

114

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“…Levine and colleges found that 3 days of i.t. GRK2 AS-ODN administration produces a 39% decrease in GRK2 protein expression in the saphenous nerve (Ferrari et al , 2012), yet we observed near-ablation of GRK2 protein at the level of the DRG. The difference in knockdown suggests that the support cells adjacent to distal portions of the afferent nerve were unaffected by i.t.…”

Section: Discussionmentioning

confidence: 63%

“…Intrathecal (i.t.) injections of GRK2 AS-ODN over 3 days significantly reduced GRK2 expression in peripheral sensory nerves (Ferrari et al , 2012). Utilizing the same AS-ODN in this study, daily i.t.…”

Section: Resultsmentioning

confidence: 99%

GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

et al. 2016

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Summary Opioids remain the standard for analgesic care, however adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally-restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G Protein-Coupled Receptor Kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf Kinase Inhibitory Protein (RKIP). Protein kinase C (PKC)-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.

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“…Through this same regulation of p38, GRK2 exacerbates brain damage in hypoxic-ischemic injury (Nijboer et al, 2010). The importance of GRK2 in this system is highlighted in that even a transient decrease in GRK2 levels (by intrathecal injection of GRK2 antisense oligodeoxynucleotides) is sufficient to produce long-lasting neuroplastic changes in nociceptor function that can lead to chronic pain (Ferrari et al, 2012). …”

Section: Grks In Inflammatory Signaling and Diseasementioning

confidence: 99%

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

Steury

McCabe

Parameswaran

2017

Advances in Immunology

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G-protein coupled receptor kinases (GRKs) are serine/threonine kinases that regulate a large and diverse class of G-protein coupled receptors (GPCRs). Through GRK phosphorylation and β-arrestin recruitment GPCRs are desensitized and their signal terminated. Recent work on these kinases has expanded their role from canonical GPCR regulation to include non-canonical regulation of non-GPCR and non-receptor substrates through phosphorylation as well as via scaffolding functions. Due to these and other regulatory roles, GRKs have been shown to play a critical role in the outcome of a variety of physiological and pathophysiological processes including chemotaxis, signaling, migration, inflammatory gene expression, etc. This diverse set of functions for these proteins makes them popular targets for therapeutics. Role for these kinases in inflammation and inflammatory disease is an evolving area of research currently pursued in many laboratories. In this review, we describe the current state of knowledge on various GRKs pertaining to their role in inflammation and inflammatory diseases.

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Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain

Cited by 49 publications

References 52 publications

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

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