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Role of D4 dopamine receptors in schizophrenia and attention
My research focus has been directed toward understanding the molecular basis of transmembrane signaling by G protein-coupled receptors. This includes the study of their structure using three-dimensional molecular graphics and modeling how the binding of various drugs causes a shift in their conformational state. We are particularly interested in the spontaneous activity exhibited by some receptors. In the case of D4 dopamine receptors we have characterized their conformation-dependent participation in the process of phospholipid methylation, a unique and novel mechanism of signaling. A cycle of D4 receptor-mediated phospholipid methylation requires resupply of a new methyl group from the single carbon folate pool, thereby linking activity of the D4 receptor to folate-dependent pathways of cellular metabolism. Different methylation states of the D4 receptor exhibit various degrees of spontaneous activity with regard to G protein coupling. Deficits in D4 receptor-mediated phospholipid methylation may contribute to the etiology of several neuropsychiatric disorders, including schizophrenia and depression.
Deth, R.C. “Molecular Origins of Attention: The Dopamine-Folate Connection” Kluwer Academic Publishers (2003)
Zhu Q., Qi, L-J., Abou-Samra, A., Shi, A. and Deth, R.C.: “Protein kinase C-dependent constitutive activity of a2A/D-adrenergic receptors.” Pharmacol. 71: 80-90 (2004).
Waly, M., Banerjee, R., Choi, S.W., Mason, J., Benzecry, J., Power-Charnitsky, V.A, Deth, R.C. “PI3-kinase regulates methionine synthase: Activation by IGF-1 or dopamine and inhibition by heavy metals and thimerosal” Molecular Psychiatry 9: 358-370 (2004).
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