COMT gene locus
| Autor: | Richard Ohrbach, Célia Marisa Rizzatti-Barbosa, Shad B. Smith, Samantha K. Segall, William Maixner, Roger B. Fillingim, Charles Knott, Pekka T. Männistö, Marc Parisien, Douglas Tsao, Josee Gauthier, Joel D. Greenspan, Marjo Piltonen, Carolina B. Meloto, Marino Convertino, Dmitri V. Zaykin, Luda Diatchenko, Ilkka Reenilä, Svetlana A. Shabalina, Nikolay V. Dokholyan, Gary D. Slade |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Chronic pain Cohort Studies Neuroblastoma 0302 clinical medicine Catecholaminergic Genetics 0303 health sciences Dopaminergic Brain Temporomandibular Joint Disorders 3. Good health Association study Phenotype Neurology Female Research Paper Pain Threshold Gene isoform Pain Locus (genetics) Biology Catechol O-Methyltransferase Transfection Polymorphism Single Nucleotide behavioral disciplines and activities 03 medical and health sciences Cell Line Tumor mental disorders medicine Humans RNA Messenger Allele Functional polymorphism 030304 developmental biology Catechol-O-methyl transferase organic chemicals fungi Genetic Variation medicine.disease COMT Anesthesiology and Pain Medicine Gene Expression Regulation nervous system Genetic marker Case-Control Studies bacteria Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Pain |
| ISSN: | 0304-3959 |
| Popis: | Supplemental Digital Content is Available in the Text. A catechol-O-methyltransferase genetic marker of pain led to the discovery of an alternative enzyme that acts through dopamine rather than epinephrine, characteristic of reference catechol-O-methyltransferase. 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. |
| Databáze: | OpenAIRE |
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