Compartmentalized NRG signaling and PDZ domain‐containing proteins in synapse structure and function

Huang, Yang; Wang, Qiang; Won, Sandra; Luo, Zhen-Ge; Xiong, Wen Cheng; Mei, Lin

doi:10.1016/s0736-5748(02)00011-4

Cited by 28 publications

(33 citation statements)

References 115 publications

(150 reference statements)

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“…Consistent with other investigators, we have demonstrated the expression and localization of ErbB2, ErbB3, and ErbB4 proteins in skeletal muscle and the enrichment of these receptors at the NMJ (2,14,15,25,40,48). A novel finding in our study is the increased expression of ErbB3 in the EDL, a predominantly fasttwitch, glycolytic muscle compared with the soleus, a predominantly slow-twitch, oxidative muscle.…”

Section: Discussionsupporting

confidence: 92%

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

LeBrasseur

Coté

Miller

et al. 2003

American Journal of Physiology-Cell Physiology

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(NRG) and the ErbB receptors in skeletal muscle biology include myogenesis, ACh receptor expression, and glucose transport. To date, however, the physiological regulation of NRG/ErbB signaling has not been examined. We tested the hypothesis that contractile activity in vivo induces NRG/ ErbB activation. Rat hindlimb muscle contraction was elicited with a single bout of electrical stimulation (RX) or treadmill running (EX). Western blot and immunofluorescence confirmed the expression of multiple NRG isoforms and the ErbB2, ErbB3, and ErbB4 receptors in adult skeletal muscle. Both RX and EX significantly increased phosphorylation of all NRG receptors. Furthermore, contraction induced a shift in the expression profile of NRG, consistent with proteolytic processing of a transmembrane isoform. Thus two distinct modes of exercise activated processing of NRG with concomitant stimulation of ErbB2, ErbB3, and ErbB4 signaling in vivo. To our knowledge, this is the first demonstration of physiological regulation of NRG/ErbB signaling in any organ and implicates this pathway in the metabolic and proliferative responses of skeletal muscle to exercise. exercise; growth factor; receptor tyrosine kinase THE PROLIFERATIVE AND METABOLIC responses of skeletal muscle to contractile activity involve the complex integration of both intra-and intercellular signaling pathways. The activation of diverse intracellular kinase cascades has been demonstrated in skeletal muscle, and these have been associated with fiber hypertrophy and alterations in metabolism. The extracellular stimuli and cell-cell interactions that trigger the activation of these pathways during and after exercise, however, have not been elucidated. In multiple cell types, growth factors relay key extracellular signals to trigger diverse cellular events via receptor tyrosine kinases (RTKs) (9). One such candidate system in the regulation of exercise signaling that has pleiotrophic effects in skeletal muscle is neuregulin (NRG) and its cognate RTKs ErbB2, ErbB3, and ErbB4.The NRGs (also known as heregulin, neu differentiation factor, ACh receptor-inducing activity, glial growth factor II, and sensory motor neuron-derived factor) are a complex family of proteins structurally related to the classical polypeptide mitogen-epidermal growth factor (EGF; see Ref. 19). More than 15 distinct soluble and membrane-anchored NRG isoforms result from alternative splicing of mRNA from one of four known NRG genes (21). All NRGs identified to date feature an EGF-like motif that is both necessary and sufficient for biological activity (6, 29). NRG signals are mediated via activation of the type I subfamily RTKs: ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4) (7,13, 30,41). Heteromeric complexes of ErbB2, ErbB3, and ErbB4 and homomeric ErbB4 are activated by NRG binding and lead to phosphorylation of cytoplasmic tyrosine residues that initiate a diverse array of downstream signaling events (5, 46).NRGs activate growth, differentiation, and survival signaling pathways in multiple cell ty...

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Section: Discussionsupporting

confidence: 92%

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

LeBrasseur

Coté

Miller

et al. 2003

American Journal of Physiology-Cell Physiology

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“…The demonstration that the SAPAPs are present at several types of excitatory synapses is consistent with the possibility that the SAPAP proteins are a general "core" component of all excitatory synapses. Moreover, PSD-95 family proteins have been found at neuronal cholinergic synapses (Conroy et al, 2003;Parker et al, 2003), and there have also been reports that PSD-95 and SAP97 are located at the neuromuscular junction (Rafael et al, 1998;Huang et al, 2002). Together, these observations suggest that there may be an entire "core" postsynaptic complex that is generally required for the structure and/or function of all excitatory synapses.…”

Section: Discussionmentioning

confidence: 99%

Differential mRNA expression and protein localization of the SAP90/PSD‐95–associated proteins (SAPAPs) in the nervous system of the mouse

Welch

Wang

Feng

2004

J of Comparative Neurology

105

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The supramolecular anchoring/signaling complex at the postsynaptic density of glutamatergic synapses has been proposed to play a key role in regulating synaptic function and plasticity. One class of proteins present in the complex is the SAP90/PSD-95-associated protein family (SAPAPs). The SAPAPs, identified by their direct interaction with PSD-95 family proteins, were initially proposed to function in the anchoring/signaling complex as linker proteins between glutamate receptor binding proteins and the cytoskeleton. However, recent studies have indicated that the SAPAPs also bind to signaling molecules and may thus have multiple roles at synapses. Four homologous genes encoding SAPAP proteins have been previously identified. As a first step toward understanding the physiological function of the SAPAPs, we have investigated in detail, at both the mRNA and protein levels, the localization of the individual SAPAP genes in the adult murine nervous system. We find that the SAPAP mRNAs are highly, yet differentially, expressed in many regions of the brain, including the hippocampus and cerebellum. Furthermore, SAPAP3 mRNA is targeted to dendrites, whereas SAPAP1, -2, and -4 mRNAs are detected mainly in cell bodies. The SAPAP proteins are localized at synapses in a manner consistent with mRNA expression. Surprisingly, in addition to glutamatergic synapse localization, antibody staining also reveals that the SAPAP proteins are localized at cholinergic synapses, including neuronal cholinergic synapses and the neuromuscular junction. Together, these results indicate that the SAPAPs are general components of excitatory synapses and that each of these proteins may perform a distinct function.

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“…Mutations in dlg-/-cause dramatic defects in the formation of septate junctions between epithelial cells [47,49] and of the larval NMJ [48] (see below). Four vertebrate homolog of DLG have been described, SAP90/PSD-95, SAP102, SAP97/hDlg and Chapsyn-110/PSD93 [5], all of which have been localized to CNS glutamatergic synapses (see [9,50]) as well as at cholinergic synapses of the CNS [51] and NMJ [52]. Of these, SAP97/hDlg is the most broadly expressed and is found in nearly every tissue and cell type.…”

Section: Members Of the Maguk Superfamilymentioning

confidence: 99%

MAGUKs in synapse assembly and function: an emerging view

Montgomery

Zamorano

Garner

2004

Cellular and Molecular Life Sciences (CMLS)

113

105

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Neuronal morphogenesis, synaptogenesis and synaptic plasticity are fundamental aspects of nervous system development. Much of our current understanding of how each of these processes contributes to the establishment and maintenance of neural circuitry has come from a molecular description of specific classes of key molecules. With regard to synapse assembly and function, a family of membrane-associated guanylate kinase homologs (MAGUKs) have emerged as central organizers of multicomponent protein signaling complexes. In particular MAGUKs appear to play fundamental roles in the transport, anchoring and signaling of specific subclasses of synaptic receptors and ion channels. In this review, we will focus on the role that subfamilies of MAGUKs play during the formation, maintenance and plasticity of the vertebrate central nervous system glutamatergic synapse.

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Compartmentalized NRG signaling and PDZ domain‐containing proteins in synapse structure and function

Cited by 28 publications

References 115 publications

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle

Differential mRNA expression and protein localization of the SAP90/PSD‐95–associated proteins (SAPAPs) in the nervous system of the mouse

MAGUKs in synapse assembly and function: an emerging view

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