Papers of the Week

Voltage-gated T-type Ca (Cav3) channels regulate diverse physiological events including neuronal excitability and have been linked to several pathological conditions such as absence epilepsy, cardiovascular diseases, and neuropathic pain. It is also acknowledged that Ca/Calmodulin-dependent protein kinase II (CaMKII) and protein kinases A and C (PKA and PKC) regulate the activity of T-type channels. Interestingly, peripheral nerve injury induces tactile allodynia and up-regulates Cav3.2 channels and Cdk5 in dorsal root ganglia (DRG) and spinal dorsal horn (SDH). Here, we report that recombinant Cav3.2 channels expressed in HEK-293 cells are regulatory targets of cyclin-dependent kinase 5 (Cdk5). Site-directed mutagenesis showed that the relevant sites for this regulation are residues S561 and S1987. We also found that Cdk5 may regulate Cav3.2 channel functional expression in rats with mechanical allodynia induced by spinal nerve ligation (SNL). Consequently, the Cdk5 inhibitor olomoucine affected the compound action potential (cAP) recorded in the spinal nerves, as well as the paw withdrawal threshold. Likewise, Cdk5 expression was upregulated after SNL in the DRGs. These findings unveil a novel mechanism for how phosphorylation may regulate Cav3.2 channels and suggest that increased channel activity by Cdk5-mediated phosphorylation after SNL contributes nerve injury-induced tactile allodynia.Neuropathic pain is a current public health challenge. It can develop as a result of injury or nerve illness. It is acknowledged that the expression of various ion channels can be altered in neuropathic pain, including T-type Ca channels that are expressed in sensory neurons where they play a role in the regulation of cellular excitability. The present work shows that the exacerbated expression of Cdk5 in a preclinical model of neuropathic pain increases the functional expression of Cav3.2 channels. This finding is relevant for the understanding of the molecular pathophysiology of the disease. Additionally, this work may have a substantial translational impact, since it describes a novel molecular pathway that could represent an interesting therapeutic alternative for neuropathic pain.