The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by post-translational modifications (PTM), creating a code that controls protein function in time and space. Phosphorylation is an important PTM that affects ∼30% of proteins in vivo. Increased phosphorylation of various nociceptive ion channels and of their modulators underlies sensitization of different pain states. Cyclin-dependent kinases are proline-directed serine/threonine kinases that impact various biological and cellular systems. Cdk5, one member of this kinase family, and its activators p35 and p39 are expressed in spinal nerves, dorsal root ganglia and in the dorsal horn of the spinal cord. In neuropathic pain conditions expression and/or activity of Cdk5 is increased, implicating Cdk5 in nociception. Experimental evidence suggests that Cdk5 is regulated via its own phosphorylation, through increasing p35’s interaction with Cdk5, and via cleavage of p35 into p25. This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5-substrates that have been linked to nociceptive pathways, including channels (e.g., transient receptor potential cation channel, voltage-gated calcium channel), proteins involved in neurotransmitter release (e.g., synaptophysin, collapsin response mediator protein 2), and receptors (e.g., glutamate, purinergic, and opioid). By altering the phosphoregulatory “set-point” of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.

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PubMed