부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S2005-2901(09)60011-X Byline: Kjell Fuxe (a), Daniel Marcellino (a), Diego Guidolin (b), Amina S. Woods (c), Luigi Agnati (d) Keywords: allosteric mechanisms; G protein-coupled receptors; integrative signaling; neuropsychopharmacology; receptor heteromer; receptor mosaic Abstract: The concept of intramembrane receptor-receptor interactions and evidence for their existence was introduced by Agnati and Fuxe in 1980/81 suggesting the existence of heteromerization of receptors. In 1982, they proposed the existence of aggregates of multiple receptors in the plasma membrane and coined the term receptor mosaics (RM). In this way, cell signaling becomes a branched process beginning at the level of receptor recognition at the plasma membrane where receptors can directly modify the ligand recognition and signaling capacity of the receptors within a RM. Receptor-receptor interactions in RM are classified as operating either with classical cooperativity, when consisting of homomers or heteromers of similar receptor subtypes having the same transmitter, or non-classical cooperativity, when consisting of heteromers. It has been shown that information processing within a RM depends not only on its receptor composition, but also on the topology and the order of receptor activation determined by the concentrations of the ligands and the receptor properties. The general function of RM has also been demonstrated to depend on allosteric regulators (e.g., homocysteine) of the receptor subtypes present. RM as integrative nodes for receptor-receptor interactions in conjunction with membrane associated proteins may form horizontal molecular networks in the plasma membrane coordinating the activity of multiple effector systems modulating the excitability and gene expression of the cells. The key role of electrostatic epitope-epitope interactions will be discussed for the formation of the RM. These interactions probably represent a general molecular mechanism for receptor-receptor interactions and, without a doubt, indicate a role for phosphorylation-dephosphorylation events in these interactions. The novel therapeutic aspects given by the RMs will be discussed in the frame of molecular neurology and psychiatry and combined drug therapy appears as the future way to go. Author Affiliation: (a) Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, Stockholm, Sweden (b) Department of Anatomy and Physiology, University of Padua, Padua, Italy (c) National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA (d) Department of Biomedical Sciences, University of Modena, Modena, and IRCCS, Lido Venice, Italy Article History: Received 16 December 2008; Accepted 6 January 2009