J. Neurosci. -- eLetters for Krämer et al., 27 (51) 14190-14198

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BehavioralSystemsCognitive:
Ulrike M. Krämer, Toni Cunillera, Estela Càmara, Josep Marco-Pallarés, David Cucurell, Wido Nager, Peter Bauer, Rebecca Schüle, Ludger Schöls, Antoni Rodriguez-Fornells, and Thomas F. Münte
The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring
J. Neurosci. 2007; 27: 14190-14198 [Abstract] [Full text] [PDF]

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The COMT conundrum
Claudia Wolf, David E. Linden (25 January 2008)

The COMT conundrum 25 January 2008

Claudia Wolf,
PhD student
Bangor LL572AS, Wales, UK,
David E. Linden
Send letter to journal:
Re: The COMT conundrum

psp205{at}bangor.ac.uk Claudia Wolf, et al.

The statement “COMT is a major enzyme in dopamine degradation particularly in prefrontal areas because of a lack of the dopamine transporter in this region” (Krämer et al., 2007) reflects a common misconception about the role of this enzyme in catecholamine metabolism. Most available evidence suggests that both isoforms of COMT are intracellular. More specifically, the membrane-bound MB-COMT has been localised to the rough endoplasmatic reticulum, and the soluble S-COMT to the cytosol and nucleus (Ulmanen et al., 1997). If COMT is inside the cell the enzyme’s access to synaptic dopamine depends on the availability of a reuptake mechanism. The lack of dopamine transporter in prefrontal cortex would thus severely limit the function of COMT if it was not for the norepinephrine transporter, which also transports dopamine (Horn, 1973) and has an even higher affinity for dopamine than the dopamine transporter (Eshlemann et al., 1999; Gu et al., 1994). Further, the reduced number of dopamine transporters in the prefrontal cortex seems to be overcome by the higher expression of norepinephrine transporters (Moll et al., 2000). Recent evidence suggests that dopamine reuptake in prefrontal cortex indeed depends primarily on the norepinephrine transporter (Morón et al., 2002).
COMT does seem to play an important role in prefrontal cortex, judging from the expression of its mRNA, which is higher than in the striatum (Matsumoto et al., 2003). It is thus tempting to reformulate the above sentence into “COMT is a major enzyme in prefrontal areas despite a lack of the dopamine transporter in this region”.
References
Eshlemann AJ, Carmolli M, Cumbay M, Martens CR, Neve KA, Janowsky A (1999)Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J Pharmacology and Experimental Therapeutics 289:877-885.
Gu H, Wall SC, Rudnick G (1994) Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J Biol Chem 269:7124-7130.
Horn AS (1973) Structure-activity relations for inhibition of catecholamine uptake into synaptosomes from noradrenaline and dopaminergic neurones in rat brain homogenates. Br J Pharmac 47:332-338.
Krämer UM, Cunillera T, Càmara E, Marco-Pallarés J, Cucurell D, Nager W, Bauer P, Schüle R, Schlös L, Rodrguez-Fornells A, Münte TF (2007) The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring. J Neurosci 27:14190-14198.
Matsumoto M, Shannon Weickert C, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003) Catechol O-methyltransferase m-RNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116:127-137.
Moll GH, Mehnert C, Wicker M, Bock N, Rothenberger A, Rüther E, Huether G 2000) Age-associated changes in the densities of presynaptic monoamine transporters in different regions of the rat brain from early juvenile life to late adulthood. Develop Br Res 119:251-257.
Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter: evidence from knock-out mouse lines. J Neurosci 22: 389-395.
Ulmanen I, Peränen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry J-P, Lundström K (1997) Expression and intracellular localization of catechol O-methyltransferase in transfected mammalian cells. Eur J Biochem 243:452-459.
Claudia Wolf (psp205@bangor.ac.uk) and David E. J. Linden (d.linden@bangor.ac.uk) Wolfson Centre for Clinical and Cognitive Neuroscience, School of Psychology, Bangor University, Bangor LL57 2AS, Wales, U.K. D.L. is funded by The Wellcome Trust, grant number 077185/Z/05/Z.