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Molecular approaches for manipulating astrocytic signaling in vivo.

Xie AX, Petravicz J, McCarthy KD - Front Cell Neurosci (2015)

Bottom Line: Astrocytes exhibit complex signaling systems that are essential for their normal function and the homeostasis of the neural network.To further understand astrocyte function in health and disease, it is important to study astrocytic signaling in vivo.Lastly, we highlight a few tools in development that present strong potential for advancing our understanding of the role of astrocytes in physiology, behavior, and pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

ABSTRACT
Astrocytes are the predominant glial type in the central nervous system and play important roles in assisting neuronal function and network activity. Astrocytes exhibit complex signaling systems that are essential for their normal function and the homeostasis of the neural network. Altered signaling in astrocytes is closely associated with neurological and psychiatric diseases, suggesting tremendous therapeutic potential of these cells. To further understand astrocyte function in health and disease, it is important to study astrocytic signaling in vivo. In this review, we discuss molecular tools that enable the selective manipulation of astrocytic signaling, including the tools to selectively activate and inactivate astrocyte signaling in vivo. Lastly, we highlight a few tools in development that present strong potential for advancing our understanding of the role of astrocytes in physiology, behavior, and pathology.

No MeSH data available.


Related in: MedlinePlus

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).
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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).

Mentions: By far, the emphasis in astrocyte GPCR signaling activity has been on the regulation of Ca2+. This is not surprising given that Ca2+ fluxes play a very important role in regulating biological processes and Ca2+ is the only signaling molecule that we can readily monitor selectively in astrocytes in complex tissue such as brain. Consequently, we know a lot about astrocyte Ca2+ responses following the activation of Gq-GPCRs and the consequences of increasing astrocyte Ca2+ by a number of different approaches. Two important points need to be kept in mind when considering findings in this area. First, most investigations linking increases in astrocyte Ca2+ with functional responses use pharmacological methods to increase astrocyte Ca2+ and consequently findings may not reflect physiological responses. Second, while the field has focused on the role of astrocyte Ca2+ in functional responses, the activation of Gq-coupled GPCRs leads to the modulation of a broad set of signaling cascades beyond changes in Ca2+; the variety of effector proteins in Gαq “interactome” may affect astrocyte Ca2+ responses as well as play important roles in physiological responses to Gq-GPCR activation (Figure 1; Sanchez-Fernandez et al., 2014).


Molecular approaches for manipulating astrocytic signaling in vivo.

Xie AX, Petravicz J, McCarthy KD - Front Cell Neurosci (2015)

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).
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Related In: Results  -  Collection

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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).
Mentions: By far, the emphasis in astrocyte GPCR signaling activity has been on the regulation of Ca2+. This is not surprising given that Ca2+ fluxes play a very important role in regulating biological processes and Ca2+ is the only signaling molecule that we can readily monitor selectively in astrocytes in complex tissue such as brain. Consequently, we know a lot about astrocyte Ca2+ responses following the activation of Gq-GPCRs and the consequences of increasing astrocyte Ca2+ by a number of different approaches. Two important points need to be kept in mind when considering findings in this area. First, most investigations linking increases in astrocyte Ca2+ with functional responses use pharmacological methods to increase astrocyte Ca2+ and consequently findings may not reflect physiological responses. Second, while the field has focused on the role of astrocyte Ca2+ in functional responses, the activation of Gq-coupled GPCRs leads to the modulation of a broad set of signaling cascades beyond changes in Ca2+; the variety of effector proteins in Gαq “interactome” may affect astrocyte Ca2+ responses as well as play important roles in physiological responses to Gq-GPCR activation (Figure 1; Sanchez-Fernandez et al., 2014).

Bottom Line: Astrocytes exhibit complex signaling systems that are essential for their normal function and the homeostasis of the neural network.To further understand astrocyte function in health and disease, it is important to study astrocytic signaling in vivo.Lastly, we highlight a few tools in development that present strong potential for advancing our understanding of the role of astrocytes in physiology, behavior, and pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

ABSTRACT
Astrocytes are the predominant glial type in the central nervous system and play important roles in assisting neuronal function and network activity. Astrocytes exhibit complex signaling systems that are essential for their normal function and the homeostasis of the neural network. Altered signaling in astrocytes is closely associated with neurological and psychiatric diseases, suggesting tremendous therapeutic potential of these cells. To further understand astrocyte function in health and disease, it is important to study astrocytic signaling in vivo. In this review, we discuss molecular tools that enable the selective manipulation of astrocytic signaling, including the tools to selectively activate and inactivate astrocyte signaling in vivo. Lastly, we highlight a few tools in development that present strong potential for advancing our understanding of the role of astrocytes in physiology, behavior, and pathology.

No MeSH data available.


Related in: MedlinePlus