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Pharmacology of cell adhesion molecules of the nervous system - PubMed

Pharmacology of cell adhesion molecules of the nervous system

Darya Kiryushko et al. Curr Neuropharmacol. 2007 Dec.

Abstract

Cell adhesion molecules (CAMs) play a pivotal role in the development and maintenance of the nervous system under normal conditions. They also are involved in numerous pathological processes such as inflammation, degenerative disorders, and cancer, making them attractive targets for drug development. The majority of CAMs are signal transducing receptors. CAM-induced intracellular signalling is triggered via homophilic (CAM-CAM) and heterophilic (CAM - other counter-receptors) interactions, which both can be targeted pharmacologically. We here describe the progress in the CAM pharmacology focusing on cadherins and CAMs of the immunoglobulin (Ig) superfamily, such as NCAM and L1. Structural basis of CAM-mediated cell adhesion and CAM-induced signalling are outlined. Different pharmacological approaches to study functions of CAMs are presented including the use of specific antibodies, recombinant proteins, and synthetic peptides. We also discuss how unravelling of the 3D structure of CAMs provides novel pharmacological tools for dissection of CAM-induced signalling pathways and offers therapeutic opportunities for a range of neurological disorders.

Keywords: L1; NCAM; Recombinant; cadherin; ligand; peptide; pharmacology..

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Figures

Fig. (1)
Fig. (1)

Structural basis of CAM-mediated cell adhesion. (A)Domain structure of classic and proto- cadherins, L1, and NCAM 180/140. Binding partners for cytoplasmic tails of CAMs are shown. (B) A model of cadherin-mediated cell adhesion (shown for N-cadherin). (C) Two proposed mechanisms of homophilic L1 binding. Note that the cartoon of L1 is shortened to highlight Ig1-Ig6. The horseshoe (I) and the extended (II) conformations of L1 exist in dynamic equilibrium and may underlie two different mechanisms of homophilic L1 binding, occurring in the cooperative (1) or modular (2) mode. See text for details. (D)A model of homophilic NCAM binding. Top: crystal structure of NCAM Ig1-Ig2-Ig3 showing interaction between the three Ig-modules. Bottom: organization of the extracellular part of NCAM molecules engaged in both a flat and a compact zipper. The large ellipsoids correspond to the two interacting Ig1-Ig2-Ig3 constructs as shown in the leftmost part (modified from [73]).

Fig. (2)
Fig. (2)

Intracellular signalling by CAMs. Signal transduction pathways associated with FGFR (A) and cytoplasmic parts of cadherins (B), L1-CAM (C), and NCAM (D). Stippled arrows indicate weak interactions and/or putative signalling links. See text for details.

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