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Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain.

ABSTRACT: We previously demonstrated that the chemokine receptor CXCR4 plays an important role in cancer-induced bone pain by activating spinal neurons and glial cells. However, the specific neuronal mechanism of CXCR4 signaling is not clear. We further report that CXCR4 contributes to the activation of the neuronal CaMKII/CREB pathway in cancer-induced bone pain. We used a tumor cell implantation (TCI) model and observed that CXCR4, p-CaMKII and p-CREB were persistently up-regulated in spinal neurons. CXCR4 also co-expressed with p-CaMKII and p-CREB, and mediated p-CaMKII and p-CREB expression after TCI. Intrathecal delivery of CXCR4 siRNA or CaMKII inhibitor AIP2 abrogated TCI-induced pain hypersensitivity and TCI-induced increase in p-CaMKII and p-CREB expression. Intrathecal injection of the principal ligand for CXCR4, SDF-1, promoted p-CaMKII and p-CREB expression in naive rats, which was prevented by post-administration of CXCR4 inhibitor Plerixafor or PLC inhibitor U73122. Plerixafor, U73122, or AIP2 also alleviated SDF-1-elicited pain behaviors. Intrathecal injection of CXCR4 siRNA significantly suppressed TCI-induced up-regulation of NMDAR1 mRNA and protein, which is a known gene target of CREB. Collectively, these results suggest that the CaMKII/CREB pathway in spinal neurons mediates CXCR4-facilitated pain hypersensitivity in cancer rats.

SUBMITTER: Hu XM

PROVIDER: S-EPMC5479786 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain.

Hu Xue-Ming XM Zhang Hui H Xu Heng H Zhang Hai-Long HL Chen Li-Ping LP Cui Wen-Qiang WQ Yang Wei W Shen Wen W

Scientific reports 20170621 1

We previously demonstrated that the chemokine receptor CXCR4 plays an important role in cancer-induced bone pain by activating spinal neurons and glial cells. However, the specific neuronal mechanism of CXCR4 signaling is not clear. We further report that CXCR4 contributes to the activation of the neuronal CaMKII/CREB pathway in cancer-induced bone pain. We used a tumor cell implantation (TCI) model and observed that CXCR4, p-CaMKII and p-CREB were persistently up-regulated in spinal neurons. CX ...[more]

PMID: 28638088

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Project description:Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).

Dataset Information

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain.

Publications

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain.

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