Pharmacological interactions between calcium/calmodulin-dependent kinase II alpha and TRPV1 receptors in rat trigeminal sensory neurons.
Multiple lines of evidence suggest that calcium/calmodulin-dependent kinase II alpha (CaMKIIalpha) plays an important role in the spinal dorsal horn in nociceptive models of chemical, inflammatory and nerve injury. Moreover, CaMKIIalpha phosphorylates the vanilloid receptor type 1 (TRPV1), thereby regulating vanilloid agonist binding to the receptor. Herein, we have explored a possible interaction of CaMKIIalpha activity with the TRPV1 receptor in rat trigeminal ganglion (TG) neurons in vitro. Inhibition of CaMKIIalpha with KN-93 (5 microM) inhibited capsaicin (CAP)- and n-arachidonoyl-dopamine (NADA)-evoked calcitonin gene-related peptide (CGRP) release effectively decreasing the Emax for both compounds. This effect was not mimicked by the inactive compound KN-92 (5 microM), indicating that the effect was mediated by CaMKIIalpha inhibition. CAP also stimulated a significant approximately 50% increase in autophosphorylation of CaMKIIalpha at Thr286/287. Immunocytochemistry for phospho-CaMKIIalpha indicated that this effect specifically occurred in TRPV1-positive TG neurons. These findings indicate that phopho-CaMKIIalpha is likely to play a role in presynaptic primary afferents in animal models of nociceptive hypersensitivity and provide support for CaMKIIalpha modulation of TRPV1 activity in sensory neurons.
Price
Theodore J
TJ
The University of Texas Health Science Center at San Antonio, Department of Endodontics, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. theodore.price@mcgill.ca
Jeske
Nathanial A
NA
Flores
Christopher M
CM
Hargreaves
Kenneth M
KM
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004298:Dopamine / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010146:Pain / Q000201:enzymology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C474941:arachidonyl dopamine; D013912:Threonine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517675:Camk2a protein, rat; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D004298:Dopamine