Integrins as receptor targets for neurological disorders

Abstract

This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell-ECM and cell-cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca(2+) and protein kinase signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders.

Figure 1. Schematic diagram for integrin-mediated signaling pathways

Integrins mediate cell– extracellular matrix (ECM) and cell–cell adhesion events through binding ECM proteins such as fibronectin and transmembrane proteins such as cell adhesion molecules (CAMs) on adjacent cells. The ECM-integrin system consists of extracellular matrix (ECM) proteins, integrins and focal adhesion complex (FAC) that includes non-receptor tyrosine kinases (NRTK) and cytoskeleton (CSK) proteins. In this model, integrin clustering by multivalent ligands, including ECM proteins, induces recruitment of CSK proteins such as talin, vinculin, actin, tubulin, actinin, paxillin and tensin, and NRTK such as focal adhesion kinase (FAK) and Src to the focal contact. Integrin-linked kinase (ILK), phospholipase C (PLC), inositol trisphosphate (IP3), diglyceride (DAG), protein kiase A (PKA), PKC, PKG, Raf, GTPase (e.g. Ras, Cdc42, Rac, SOS and C3G), mitogen-activated protein kinase (MEK), extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), as well as adaptor proteins such as Grb2, Crk, and Sos, are also recruited to the ECM-integrin binding site. Integrins also mediate crosstalk with other cell surface receptors such as growth factor receptor (GFR), cadherins and cell adhesion molecules (CAMs). ECM-integrin-FAC interactions play an important role in modulation of ion channels, synaptic transmission, and neuroplasticity that modulates neuronal cell proliferation, differentiation, apoptosis and migration. Integrins play an important role in pathological processes such as inflammation, wound healing, epileptogenesis, angiogenesis, and tumor metastasis.

Figure 2. Integrin subunits distribution in different regions of central nervous system

Data compiled from: (Chan, et al., 2003; Chun, et al., 2001; Glukhova & Koteliansky, 1995; Moiseeva, 2001; Morini & Becchetti, 2010; Pinkstaff, et al., 1999; Ross & Borg, 2001; Velling, et al., 1999; Wu, et al., 2010b). Individual integrin reported in one species perhaps not in others indicated in parentheses.