Abstract
Cyclin-dependent kinase 5 is a proline-directed serine/threonine kinase and its activity participates in the regulation of nociceptive signaling. Like binding with the activators (P35 or P25), the phosphorylation of Cdk5 plays a critical role in Cdk5 activation. However, it is still unclear whether Cdk5 phosphorylation (p-Cdk5) contributes to pain hyperalgesia. The aim of our current study was to identify the roles of p-Cdk5 and its upstream regulator in response to peripheral inflammation. Complete Freund's adjuvant (CFA) injection induced acute peripheral inflammation and heat hyperalgesia, which was accompanied by sustained increases in phospho-ERK1/2 (p-ERK1/2) and phospho-Cdk5S159 (p-Cdk5S159) in the spinal cord dorsal horn (SCDH). CFA-induced p-ERK primarily colocalized with p-Cdk5S159 in superficial dorsal horn neurons. Levels in p-ERK and p-Cdk5 were also increased in the 2nd phase of hyperalgesia induced by formalin injection, which can produce acute and tonic inflammatory pain. MAP kinase kinase inhibitor U0126 intrathecal delivery significantly suppressed the elevation of p-Cdk5S159, Cdk5 activity and pain response behavior (Heat hyperalgesia, Spontaneous flinches) induced by CFA or formalin injection. Cdk5 inhibitor roscovitine intrathecal administration also suppressed CFA-induced heat hyperalgesia and Cdk5 phosphorylation, but did not attenuate ERK activation. All these findings suggested that p-Cdk5S159 regulated by ERK pathway activity may be a critical mechanism involved in the activation of Cdk5 in nociceptive spinal neurons contributes to peripheral inflammatory pain hypersensitivity.
Highlights
Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclindependent kinase family [1]
Previous studies have shown that Cdk5 was markedly activated by peripheral noxious stimuli [9,20,31], phosphorylation of Cdk5 at the site of Ser159 residue (p-Cdk5S159) increases the enzymatic activity of Cdk5 activating kinases [13,14,15], we assessed the effects of Complete Freund’s adjuvant (CFA) induced peripheral noxious stimuli on the p-Cdk5S159 levels
The time course of pCdk5S159 expression was similar to the Cdk5 activity (4-fold at 6 h and 5-fold at 1 day) induced by CFA injection according to a previous report [9], which suggested that p-Cdk5S159 may be closely associated with Cdk5 activity
Summary
Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclindependent kinase family [1]. Cdk activity plays multiple roles in neuronal development and synaptic plasticity [2,3,4,5]. Further studies suggest that high levels of Cdk, p35 or p25 expression as well as Cdk kinase activity in nociceptive primary afferent neurons contribute to pain sensitization after inflammation. As a proline-directed serine/threonine kinase, Cdk catalytic activation is influenced by the binding of the activators, and by the phosphorylation [13]. Phosphorylation at the site of serine 159 or tyrosine 15 dramatically increases Cdk activation and the Ser159 residue is the major phosphorylation target for Cdk5-activating kinases [13,14]. Residue Ser159 phosphorylation contributes to the specificity of the Cdk5-p35 interaction [15] and enhances
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