Pharmacological interactions between calcium/calmodulin-dependent kinase II α and TRPV1 receptors in rat trigeminal sensory neurons

Multiple lines of evidence suggest that calcium/calmodulin-dependent kinase II α (CaMKIIα) plays an important role in the spinal dorsal horn in nociceptive models of chemical, inflammatory and nerve injury. Moreover, CaMKIIα phosphorylates the vanilloid receptor type 1 (TRPV1), thereby regulating vanilloid agonist binding to the receptor. Herein, we have explored a possible interaction of CaMKIIα activity with the TRPV1 receptor in rat trigeminal ganglion (TG) neurons in vitro. Inhibition of CaMKIIα with KN-93 (5 μM) inhibited capsaicin (CAP)- and n-arachidonoyl-dopamine (NADA)-evoked calcitonin gene-related peptide (CGRP) release effectively decreasing the E_max for both compounds. This effect was not mimicked by the inactive compound KN-92 (5 μM), indicating that the effect was mediated by CaMKIIα inhibition. CAP also stimulated a significant ∼50% increase in autophosphorylation of CaMKIIα at Thr^286/287. Immunocytochemistry for phospho-CaMKIIα indicated that this effect specifically occurred in TRPV1-positive TG neurons. These findings indicate that phopho-CaMKIIα is likely to play a role in presynaptic primary afferents in animal models of nociceptive hypersensitivity and provide support for CaMKIIα modulation of TRPV1 activity in sensory neurons.