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. 2015 Apr 21;9:144. doi: 10.3389/fncel.2015.00144

Figure 1.

Figure 1

A fabric of signaling cascades can be activated by astrocyte Gq-GPCRs. Upon Gq-GPCR activation, Gαq subunits are known to interact with G protein-coupled receptor kinases (GRKs), β-arrestins, Rho family of guanine exchange factors (RhoGEFs) and phospholipase C (PLC) in astrocytes or astroglia. In addition, Gβγ subunits are able to regulate ion channel properties, as well as to interact with signaling molecules including cdc42, PAK-PIXα, phospholipase A (PLA), PLC, and Ras/MAPK/ERK1/2. Many of the key signaling molecules regulated by Gβγ are expressed in astrocytes or astroglia. Therefore, Gq-GPCR activation in astrocytes is likely to activate an entire fabric of downstream signaling pathways that may include (1) GRKs-mediated glutamate transporter (GLAST) localization (Nijboer et al., 2013), gene transcription (Atkinson et al., 2009), metabotropic glutamate receptor 5 (mGluR5) expression (Sorensen and Conn, 2003), and astrocytoma growth (Woerner et al., 2012); (2) β-arrestin-mediated gene silencing (McLennan et al., 2008; Miyatake et al., 2009; Zhu and Reiser, 2014); (3) RhoGEFs-mediated activation of Kinectin (Santama et al., 2004), citron kinase (Ackman et al., 2007), phospholipase D (PLD) (Burkhardt et al., 2014), diacylglycerol kinase (DGKa) (Kefas et al., 2013), Rhophilin2 (Vedrenne and Hauri, 2006; Danussi et al., 2013), Rock (Holtje et al., 2005; Lau et al., 2011), and mDia1 (Shinohara et al., 2012); (4) PLC regulation of PtdIns(3,4,5)P3 (PIP3)/protein kinase B (PKB or Akt) pathway (DiNuzzo et al., 2013; Kong et al., 2013), PtdIns(4,5)P2(PIP2)/diacylglycerol (DAG)/protein kinase C (PKC) pathway, and PIP2/Ins(1,4,5)P3(IP3) pathway. Moreover, PKC activation in astrocytes (Wang et al., 2002) engages PLD (Servitja et al., 2003), c-src tyrosine kinase (CSK) (Jo et al., 2014), glycogen synthase kinase (GSK) (Sanchez et al., 2003), and cAMP signaling. Many of these signaling pathways are known to trigger cellular responses that are important for astrocyte function including gene transcription and cell migration. Box 1. Selected PIP2-induced signaling pathways in which key molecules are expressed by astrocytes. These signaling molecules include: Epithelial sodium channel (ENaC) (Miller and Loewy, 2013), PLA2 (Ha et al., 2014), Myristoylated alanine-rich C-kinase substrate (MARCKS) (Vitkovic et al., 2005), Wiskott–Aldrich syndrome protein (WASP) (Murk et al., 2013), profilin (Molotkov et al., 2013), vinculin, talin, and paxillin (Kalman and Szabo, 2001), ERM protein family (Persson et al., 2010), α1-syntrophin (Masaki et al., 2010), ankyrin (Lee et al., 2012), adipocyte protein 2 (AP2) (Rossello et al., 2012), and clathirin (Pascual-Lucas et al., 2014).