title: Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons.
abstract: Endothelin-1 (ET-1) and bradykinin (BK) are endogenous peptides that signal through Gαq/11-protein coupled receptors (GPCRs) to produce nociceptor sensitization and pain. Both peptides activate phospholipase C to stimulate Ca(2+) accumulation, diacylglycerol production, and protein kinase C activation and are rapidly desensitized via a G-protein receptor kinase 2-dependent mechanism. However, ET-1 produces a greater response and longer lasting nocifensive behavior than BK in multiple models, indicating a potentially divergent signaling mechanism in primary afferent sensory neurons. Using cultured sensory neurons, we demonstrate significant differences in both Ca(2+) influx and Ca(2+) release from intracellular stores following ET-1 and BK treatments. As intracellular store depletion may contribute to the regulation of other signaling cascades downstream of GPCRs, we concentrated our investigation on store-operated Ca(2+) channels. Using pharmacological approaches, we identified transient receptor potential canonical channel 3 (TRPC3) as a dominant contributor to Ca(2+) influx subsequent to ET-1 treatment. On the other hand, BK treatment stimulated Orai1 activation, with only minor input from TRPC3. Taken together, data presented here suggest that ET-1 signaling targets TRPC3, generating a prolonged Ca(2+) signal that perpetuates nocifensive responses. In contrast, Orai1 dominates as the downstream target of BK receptor activation and results in transient intracellular Ca(2+) increases and abridged nocifensive responses.
authors: Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at San Antonio, TX, USA.
authors: Kalina
authors: K
authors: Szteyn
authors: Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at San Antonio, TX, USA.
authors: Ruben
authors: R
authors: Gomez
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, TX, USA.
authors: Kelly A
authors: KA
authors: Berg
authors: Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at San Antonio, TX, USA Department of Pharmacology, University of Texas Health Science Center at San Antonio, TX, USA Department of Physiology, University of Texas Health Science Center at San Antonio, TX, USA jeske@uthscsa.edu.
authors: Nathaniel A
authors: NA
authors: Jeske
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D005528:Foot; D008297:Male; D059226:Nociceptive Pain / Q000378:metabolism; D000071740:ORAI1 Protein; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D019332:Endothelin-1; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D010738:Type C Phospholipases; D001920:Bradykinin; D002118:Calcium
keywords: SOCE; bradykinin; endothelin; inflammation; pain; trigeminal neurons