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The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse

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The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse Mol Neurobiol (2010) 41:1–21 DOI 10.1007/s12035-009-8089-5 The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse Gonneke S. K. Pilgram & Saranyapin Potikanond & Richard A. Baines & Lee G. Fradkin & Jasprina N. Noordermeer Received: 24 August 2009 /Accepted: 15 October 2009 /Published online: 9 November 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Duchenne muscular dystrophy is caused by muta- Keywords Dystrophin . DGC . NMJ . CNS . PNS . Retina . tions in the dystrophin gene and is characterized by Duchenne muscular dystrophy . Mammals . Drosophila . progressive muscle wasting. A number of Duchenne patients C. elegans also present with mental retardation. The dystrophin protein is part of the highly conserved dystrophin-associated glyco- Abbreviations protein complex (DGC) which accumulates at the neuromus- ACh Acetylcholine cular junction (NMJ) and at a variety of synapses in the AChR Acetylcholine receptor peripheral and central nervous systems. Many years of Akt Protein kinase B research into the roles of the DGC in muscle have revealed BMP Bone morphogenetic protein its structural function in stabilizing the sarcolemma. In Ca2+ Calcium ion addition, the DGC also acts as a scaffold for various signaling CaMKII Ca2+/calmodulin-dependent protein kinase II pathways. Here, we discuss recent advances in understanding cGMP Cyclic guanosine monophosphate DGC roles in the nervous system, gained from studies in both CNS Central nervous system vertebrate and invertebrate model systems. From these DGC Dystrophin-associated glycoprotein complex studies, it has become clear that the DGC is important for DMD Duchenne muscular dystrophy the maturation of neurotransmitter receptor complexes and for EPSP Excitatory postsynaptic potential the regulation of neurotransmitter release at the NMJ and ERG Electroretinogram central synapses. Furthermore, roles for the DGC have been GABA γ-Aminobutyric acid established in consolidation of long-term spatial and recog- Grb2 Growth factor receptor-bound protein 2 nition memory. The challenges ahead include the integration ILM Inner limiting membrane of the behavioral and mechanistic studies and the use of this InR Insulin receptor information to identify therapeutic targets. IPSC Inhibitory postsynaptic current IPSP Inhibitory postsynaptic potential Gonneke S. K. Pilgram and Saranyapin Potikanond contributed LTD Long-term depression equally to this work. LTP Long-term potentiation G. S. K. Pilgram : S. Potikanond : L. G. Fradkin (*) : MAPK Mitogen-activated protein kinase J. N. Noordermeer (*) mEPSP Miniature EPSP Laboratory of Developmental Neurobiology, Department mIPSC Miniature IPSC of Molecular and Cell Biology, Leiden University Medical Center, mIPSP Miniature IPSP Einthovenweg 20, P.O. Box 9600, 2300 RC Leiden, The Netherlands MuSK Muscle-specific kinase e-mail: [email protected] NMJ Neuromuscular junction e-mail: [email protected] nNOS Neuronal nitric oxide synthase NO Nitric oxide R. A. Baines Faculty of Life Sciences, University of Manchester, NOS Nitric oxide synthase Manchester M13 9PT, UK OPL Outer plexiform layer 2 Mol Neurobiol (2010) 41:1–21 PI3K Phosphoinositide 3-kinases containing a ZZ domain, and a highly conserved carboxy- PKA Protein kinase A terminal region including a coiled-coil domain. PKC Protein kinase C Dystrophin is predominantly expressed in the muscula- PKG Protein kinase G ture and the nervous system (Fig. 1, Table 2, and references POMT1/2 Protein O-mannosyltransferase 1 or 2 therein). More specifically, the three distinct Dp427 PPF Paired-pulse facilitation variants that are transcribed from different promoters and STD Short-term depression have distinct first exons are expressed in skeletal muscle STP Short-term potentiation (Dp427M), throughout the brain (Dp427B) and in Purkinje UGC Utrophin-associated glycoprotein complex cells (Dp427P), respectively. Dp260 is expressed in the utrn Utrophin retina, Dp140 in brain and kidney, Dp116 in the peripheral VNC Ventral nerve cord nervous system, and Dp71 is uniformly expressed, but most prominently present throughout the mammalian brain (reviewed in [7]; Fig. 1; Table 2). In mammals, there are two proteins which are significantly homologous to dystrophin, utrophin [8], and the much shorter dystrophin- Introduction related protein 2 (DRP2) [9]. Utrophin is more ubiquitously expressed compared to dystrophin, hence its name. It is Duchenne muscular dystrophy (DMD) is a common X- found in developing skeletal and smooth muscle, the linked, fatal genetic disorder characterized by progressive nervous system, the lung, kidney, liver, spleen, and stomach muscle wasting [1]. The disease was named after the [10, 11]. French neurologist G.B.A. Duchenne who, in the mid- Many components of the DGC have been identified, 1800s, described patients that suffered not only from including the dystrobrevins (DB-α and DB-β), the syntro- muscular dystrophy but also from mental retardation [2]. A phins (α1, β1, β2, γ1, and γ2), dystroglycan (DG-α/β), major advancement in understanding the underlying cause the sarcoglycans (SG-α, SG-β, SG-γ, SG-δ, SG-ε, and SG- of DMD came in 1987, when dystrophin was identified as ζ), and sarcospan [10, 12]. Together with dystrophin, these the protein that is absent in DMD patients [3, 4]. Mental proteins form a large, molecularly heterogeneous cluster retardation occurs in approximately one third of DMD [13], known as the DGC, that differs in composition patients and is apparently dependent on the specific depending on the tissue or organs where the components location of the mutation within the dystrophin gene (in are expressed (reviewed in [10, 14–16]; Fig. 1; Table 2). mammals called the DMD gene) [5]. Despite more than two The proteins of the DGC are highly conserved between decades of intense clinical and basic research into the DMD species, although there are fewer homologs and isoforms in disease process and the interactions and roles of the the lower vertebrates, such as zebrafish, and in the dystrophin protein, a cure for the disease remains elusive invertebrates, Caenorhabditis elegans and Drosophila and treatments palliative. Thus, much remains to be learned (Table 1). about the basic biological roles of the dystrophin protein in Due to the complex and variable composition of the the musculature and in the brain. DGC, it is difficult to assign a general function to this The DMD gene is one of the largest genes in the human transmembrane complex. However, in all organisms studied genome, spanning 2.3 Mb [6]. It has three upstream thus far, the different DGCs localize to the plasma promoters that control expression of full-length dystrophin membrane (reviewed in [12]). In muscle, the DGC has Dp427 and four internal promoters which regulate expres- long been thought to be required for the stabilization of the sion of the short dystrophin isoforms, Dp260, Dp140, plasma membrane by linking the actin cytoskeleton to the Dp116, and Dp71 (reviewed at www.dmd.nl; Table 1; extracellular matrix [17]. Disruption of the DGC caused by Textbox 1 in “Appendix”). The complexity of DMD gene the absence of dystrophin consequently renders the sarco- expression, which results in multiple transcripts and protein lemma susceptible to mechanical damage during contrac- isoforms, has made understanding the functions of individ- tion and ultimately results in muscle degeneration. More ual dystrophin protein isoforms difficult. Dp427 has an recently, it has been established that the DGC also functions amino-terminal actin-binding domain, and Dp427, Dp260, as a scaffold for proteins involved in signaling, including Dp140, and Dp116 have a variable number of spectrin-like neuronal nitric oxide synthase (nNOS), phosphoinositol repeats that are predicted to form triple-helical rod-like triphosphate 2, calmodulin, and growth factor receptor- structures. Dystrophin proteins invariably bear a number of bound protein 2 (grb2; reviewed in [18]). Additional protein–protein interaction domains, some of which are evidence supports the involvement of the DGC in the extra- bound by other dystrophin-associated glycoprotein complex cellular signal-regulated kinases (ERK)/mitogen-activated (DGC) members: a WW domain, a cysteine-rich region protein kinase (MAPK) signaling cascade [19], epidermal Mol Neurobiol (2010) 41:1–21 3 Table 1 Compilation of the known DGC components in human/mice, zebrafish, C. elegans, and Drosophila DGC member Species Human/mice (www.dmd.nl) Zebrafish [180] C. elegans [33] Drosophila [32] Protein (gene) (www.zfin.org) (www.wormbase.org) (www.flybase.bio.indiana.edu) Dystrophin Long isoforms: Dp427 Long isoform: a 400-kD Dystrophin-like Long isoforms: DLP1-3 (M, B, P) dystrophin ortholog protein (dys-1) Short isoforms: Dp260, Short isoform: Dp71 Short isoforms: Dp205, Dp140, Dp116, Dp71 (DMD) (dmd) Dp186, Dp117 (Dys) Utrophin a-, b-, g-Utrophin (utrn) Utrophin (utrn) [181] DRP2 Dystrophin-related protein DRP2 [181] –– (DRP2) Dystrobrevin α-Dystrobrevin (DTNA) α-Dystrobrevin (dtna) Dystrobrevin (dyb-1) Dystrobrevin-like (Dyb) β-Dystrobrevin (DTNB) β-Dystrobrevin (dtnb) γ-Dystrobrevin (dtng) [181] Dystroglycan α/β-Dystroglycan (DAG1) α/β-Dystroglycan (dag1) Dystroglycan (dgn-1) Dystroglycan (Dg) Sarcoglycan α-, ε-, β-, γ-, δ-, α-, β-, δ-ε-, γ-, α-,β-, δ/γ- Sarcoglycan-α, Sarcoglycan-β, ζ-Sarcoglycan (SCGA-Z) ζ-Sarcoglycan Sarcoglycan Sarcoglycan-δ (Scgα, Scgβ, (α-, β-, δ/γ-sgn) Scgδ) Sarcospan Sarcospan (SSPN), Not determined –– (microspan
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