TY - JOUR
T1 - COMT gene locus
T2 - New functional variants
AU - Meloto, Carolina B.
AU - Segall, Samantha K.
AU - Smith, Shad
AU - Parisien, Marc
AU - Shabalina, Svetlana A.
AU - Rizzatti-Barbosa, Celia M.
AU - Gauthier, Josee
AU - Tsao, Douglas
AU - Convertino, Marino
AU - Piltonen, Marjo H.
AU - Slade, Gary Dmitri
AU - Fillingim, Roger B.
AU - Greenspan, Joel D.
AU - Ohrbach, Richard
AU - Knott, Charles
AU - Maixner, William
AU - Zaykin, Dmitri
AU - Dokholyan, Nikolay V.
AU - Reenila, Ilkka
AU - Mannisto, Pekka T.
AU - Diatchenko, Luda
N1 - Publisher Copyright:
© 2015 International Association for the Study of Pain.
PY - 2015/10
Y1 - 2015/10
N2 - 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 39 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 painprotective 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.
AB - 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 39 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 painprotective 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.
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U2 - 10.1097/j.pain.0000000000000273
DO - 10.1097/j.pain.0000000000000273
M3 - Article
C2 - 26207649
AN - SCOPUS:84944712945
SN - 0304-3959
VL - 156
SP - 2072
EP - 2083
JO - Pain
JF - Pain
IS - 10
ER -