These results show that integrin activation is necessary to influence the functional of other cell surface receptors and vice versa. == 2.6. such as epilepsy, trauma, and brain injury. In many cerebrovascular and neuronal diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such Vernakalant (RSD1235) as extracellular matrix (ECM) are recognized as an essential process. There has been recent Vernakalant (RSD1235) interest Rabbit polyclonal to PKNOX1 in the possible role of adhesion molecules, particularly integrins as ECM receptors, in neurological disorders because they form an important link between the ECM and the intracellular cytoskeleton (CSK) and signaling molecules (Fig. 1). In the brain, ECM proteins are synthesized and secreted into the extracellular space in a mesh-like structure by neurons and glial cells. During development and mature nervous systems, and in wound healing, the interaction between ECM and its receptor integrin has a pivotal role in maintaining structural and functional neuroplasticity. ECM and integrin aberrations are likely to contribute to imbalanced synaptic function in epilepsy, Alzheimers disease, mental retardation, schizophrenia and other conditions in the brain. (Dityatev & Schachner, 2003;Dityatev et al., 2010;Gall & Lynch, 2004;Gall et al., 2003). == Figure 1. Schematic diagram for integrin-mediated signaling pathways. == Integrins mediate cell extracellular matrix (ECM) and cellcell adhesion events through binding ECM proteins such as fibronectin and transmembrane proteins such as cell adhesion molecules (CAMs) Vernakalant (RSD1235) 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. Studies of integrin-initiated intracellular signaling have shown that integrins modulate Ca2+and K+ion channels, intracellular Ca2+concentrations, cellular contractile properties, protein kinase activity, and growth factor receptors (Barouch et al., 2000;Chan et al., 2001;Danen & Yamada, 2001;Davis et al., 2001;Davis et al., 2002;Gui et al., 2006;Hynes, 1992;Martinez-Lemus et al., 2003;Porter & Hogg, 1998;Rueckschloss & Isenberg, 2004;Waitkus-Edwards et al., 2002;Wu et al., 2011a;Wu et al., 2001;Wu et al., 1998;Wu et al., 2010b;Wu et al., 2010c;Wu et al., 2008a;Wu et al., 2008b;Yang et al., 2010;Yip & Marsh, 1997). Furthermore, ECM-integrin-CSK interactions play crucial roles in gene expression, cell proliferation, migration and differentiation, and cell survivals (Hynes, 1992;Kim et al., 2011;Schwartz, 2001;Yamada & Miyamoto, 1995). Since the discovery of the first integrin receptor for ECM protein fibronectin (FN) in Vernakalant (RSD1235) 1986 (Tamkun et al., 1986), eighteen -subunits and eight -subunits have been identified (Hynes, 2002). Interestingly, there are at least 24 distinct integrins (Reichardt & Prokop, 2011) even though there are twenty-four -subunit and nine -subunit genes in the human genome (Venter et al., 2001). A total of over 50,000 papers are published on integrins so far. Fewer than 1000 papers are in the field of neuroscience as compared to ~6000 papers in cardiovascular system, indicating that.