Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Luo, Ceng; Gangadharan, Vijayan; Bali, Kiran Kumar; Xie, Rou‐Gang; Agarwal, Nitin; Kurejová, Martina; Tappe‐Theodor, Anke; Tegeder, Irmgard; Feil, Susanne; Lewin, Gary R.; Polgár, Erika; Todd, Andrew J.; Schlossmann, Jens; Hofmann, Franz; Liu, Da-Lu; Hu, San-Jue; Feil, Robert; Kuner, Thomas; Kuner, Rohini

doi:10.1371/journal.pbio.1001283

Cited by 86 publications

(112 citation statements)

References 50 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Consistent with our observations with NO blockade (above), we observed that mice lacking Prkg1 , a key target of the NO-cGMP pathway, specifically in peripheral nociceptors (Luo et al., 2012), did not develop mechanical and thermal hypersensitivity with VEGF-A (Figure 3E). We also found several lines of evidence linking VEGF-A signaling to modulation of TRPV1, the key final effector of thermal hyperalgesia (Basbaum et al., 2009).…”

Section: Resultssupporting

confidence: 92%

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

et al. 2015

Self Cite

View full text Add to dashboard Cite

SummaryCancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.

show abstract

Section: Resultssupporting

confidence: 92%

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…In primary sensory neurons of the dorsal root ganglia, cGKI also mediates potentiation of IP3R activity through phosphorylation of the receptor, leading to increased Ca 2+ release from the ER, which is functionally linked to synaptic LTP (43). IP3R-associated cGK substrate (IRAG) is required for cGKI-mediated phosphorylation of IP3Rs (44).…”

Section: Discussionmentioning

confidence: 99%

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Kim

Titcombe

Zhang

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca 2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca 2+ -permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca 2+ -permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.LTP | Ca 2+ -permeable AMPA receptors | gene knockout | calcineurin

show abstract

“…(Hirasawa et al 2007; Hirota et al 2003) Importantly, phospholipid signaling has recently been implicated in the regulation of nociception,(Neely et al 2012) consistent with the potential importance of this candidate gene in pain perception associated with its regulation of ITPR1. (Komalavilas and Lincoln 1994; Luo et al 2012; Wagner et al 2003)…”

mentioning

confidence: 99%

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice

et al. 2017

View full text Add to dashboard Cite

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors in mice. In this report we show that DRG Car8 expression is variable across 25 naive-inbred strains of mice, and this cis-regulated eQTL (association between rs27660559, rs27706398, and rs27688767 and DRG Car8 expression; P<1×10−11) is correlated with nociceptive responses in mice. Next, we hypothesized that increasing DRG Car8 gene expression would inhibit intracellular calcium release required for morphine antinociception and might correlate with antinociceptive sensitivity of morphine and perhaps other analgesic agents. We show that mean DRG Car8 gene expression is directly related to the dose of morphine or clonidine needed to provide a half-maximal analgesic response (r=0.93, P<0.00002; r=0.83, P<0.0008, respectively), suggesting that greater DRG Car8 expression increases analgesic requirements. Finally, we show that morphine induces intracellular free calcium release using Fura 2 calcium imaging in a dose-dependent manner; and V5-Car8WT overexpression in NBL cells inhibits morphine-induced calcium increase. These findings highlight the ‘morphine paradox’ whereby morphine provides antinociception by increasing intracellular free calcium, while Car8 and other antinociceptive agents work by decreasing intracellular free calcium. This is the first study demonstrating that biologic variability associated with this cis-eQTL may contribute to differing analgesic responses through altered regulation of ITPRI-dependent calcium release in mice.

show abstract

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Abstract: Electrophysiological and behavioral experiments in mice reveal that a cGMP-dependent kinase amplifies neurotransmitter release from peripheral pain sensors, potentiates spinal synapses, and leads to exaggerated pain.

Cited by 86 publications

References 50 publications

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice

Contact Info

Product

Resources

About

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Abstract: Electrophysiological and behavioral experiments in mice reveal that a cGMP-dependent kinase amplifies neurotransmitter release from peripheral pain sensors, potentiates spinal synapses, and leads to exaggerated pain.

Cited by 86 publications

References 50 publications

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca 2+ -permeable AMPA receptors

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice

Contact Info

Product

Resources

About

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors