| Autor: |
Meloto CB; The Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA Department of Prosthesis and Periodontology, Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil Department of Medicine, Division of Gastroenterology, College of Medicine, University of Florida, Gainesville, FL, USA Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC, USA Department of Community Dentistry and Behavioral Science, University of Florida, College of Dentistry, and Pain, Research and Intervention Center of Excellence, Clinical and Translational Research Building (CTRB), Gainesville, FL, USA Department of Neural and Pain Sciences, and Brotman Facial Pain Clinic, University of Maryland School of Dentistry, Baltimore, MD, USA Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, NY, USA Battelle Memorial Institute, Battelle Centers for Public Health Research and Evaluation (CPHRE), Durham, NC, USA National Institute of Environmental Health Sciences, Durham, NC, USA Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Segall SK, Smith S, Parisien M, Shabalina SA, Rizzatti-Barbosa CM, Gauthier J, Tsao D, Convertino M, Piltonen MH, Slade GD, Fillingim RB, Greenspan JD, Ohrbach R, Knott C, Maixner W, Zaykin D, Dokholyan NV, Reenilä I, Männistö PT, Diatchenko L |
| Abstrakt: |
Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3' untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. |
