The putative agrin receptor binds ligand in a calcium-dependent manner and aggregates during agrin-induced acetylcholine receptor clustering

Nastuk, Mary A.; Lieth, Erich; Ma, Joongsoo; Cardasis, Constance A.; Moynihan, Elizabeth B.; McKechnie, Beth A.; Fallon, Justin R.

doi:10.1016/0896-6273(91)90283-6

Cited by 70 publications

(48 citation statements)

References 40 publications

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“…We next extended these in vitro experiments and asked whether or not agrin binding to the surface of living cells displays a similar isoform-dependent heparin sensitivity. Biochemically purified Torpedo agrin binds to cultured myoblasts and myotubes (33). We used the quail QM-7 cell line as a convenient source of myoblasts.…”

Section: Resultsmentioning

confidence: 99%

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Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

O'Toole

Deyst

Bowe

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Agrin is a basal lamina molecule that directs key events in postsynaptic differentiation, most notably the aggregation of acetylcholine receptors (AChRs) on the muscle cell surface. Agrin's AChR clustering activity is regulated by alternative mRNA splicing. Agrin splice forms having inserts at two sites (y and z) in the C-terminal region are highly active, but isoforms lacking these inserts are weakly active. The biochemical consequences of this alternative splicing are unknown. Here, the binding of four recombinant agrin isoforms to heparin, to a-dystroglycan (a component of an agrin receptor), and to myoblasts was tested. The presence of a four-amino acid insert at they site is necessary and sufficient to confer heparin binding ability to agrin. Moreover, the binding of agrin to a-dystroglycan is inhibited by heparin when this insert is present. Agrin binding to the cell surface showed analogous properties: heparin inhibits the binding of only those agrin isoforms containing this four-amino acid insert. The results show that alternative splicing of agrin regulates its binding to heparin and suggest that agrin's interaction with ca-dystroglycan may be modulated by cell surface glycosaminoglycans in an isoform-dependent manner.

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Section: Resultsmentioning

confidence: 99%

“…Relative agrin levels in the conditioned media were determined by two-site radioimmunoassay (RIA) as described below. AChR clustering activity of the recombinant agrin isoforms was determined as described previously (33).…”

Section: Methodsmentioning

confidence: 99%

Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

O'Toole

Deyst

Bowe

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…There are two possible explanations for the Ca 2ϩ dependence in muscle. Ca 2ϩ may influence the binding of agrin to its receptor; it has been reported that in the absence of Ca 2ϩ agrin does not bind to the myotube surface (Nastuk et al, 1991;Ma et al, 1993;Gee et al, 1994). Alternatively, engagement of the agrin receptor may trigger a signaling cascade that leads to Ca 2ϩ influx.…”

Section: Discussionmentioning

confidence: 99%

Specific Agrin Isoforms Induce cAMP Response Element Binding Protein Phosphorylation in Hippocampal Neurons

Böse

Lesuisse

et al. 1998

J. Neurosci.

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The synaptic basal lamina protein agrin is essential for the formation of neuromuscular junctions. Agrin mediates the postsynaptic clustering of acetylcholine receptors and regulates transcription in muscles. Agrin expression is not restricted to motor neurons but can be demonstrated throughout the CNS. The functional significance of agrin expression in neurons other than motor neurons is unknown. To test whether agrin triggers responses in neurons that lead to the activation of transcription factors, we have analyzed phosphorylation of the transcriptional regulatory site serine 133 of the transcription factor CREB (cAMP response element binding protein) in primary hippocampal neurons. Our results indicate that the neuronal (Ag4,8), but not the non-neuronal (Ag0,0), isoform of agrin induces CREB phosphorylation in hippocampal neurons. The kinetics of agrin-and BDNF-induced CREB phosphorylation are similar: peak levels are reached in minutes and are strongly reduced 2 hr later. Neuronal responses to agrin require extracellular calcium, and, in contrast to tyrosine kinase inhibitors, the specific inhibition of protein kinase A (PKA) does not affect agrin-evoked CREB phosphorylation. Our results show that hippocampal neurons specifically respond to neuronal agrin in a Ca 2ϩ -dependent manner and via the activation of tyrosine kinases.

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“…Chicken myotube cultures were prepared from pectoral muscle of embryonic day 11 (E11) embryos as described (25). Muscle cells were cultured on glass coverslips coated with poly-D-lysine and gelatin in minimum essential medium (alpha medium; GIBCO) supplemented with 10% horse serum, 2% chicken embryo extract, and 100 units/ml penicillin.…”

Section: Methodsmentioning

confidence: 99%

Neurotrophins regulate agrin-induced postsynaptic differentiation

Wells

McKechnie

Kelkar

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The precise orchestration of synaptic differentiation is critical for efficient information exchange in the nervous system. The nerve-muscle synapse forms in response to agrin, which is secreted from the motor nerve terminal and induces the clustering of acetylcholine receptors (AChRs) and other elements of the postsynaptic apparatus on the subjacent muscle cell surface. In view of the highly restricted spatial localization and the plasticity of neuromuscular junctions, it seems likely that synapse formation and maintenance are regulated by additional, as-yet-unidentified factors. Here, we tested whether neurotrophins modulate the agrin-induced differentiation of postsynaptic specializations. We show that both brain-derived neurotrophic factor ( The formation, maintenance, and plasticity of synaptic connections is essential for the proper functioning of the nervous system. A hallmark of fast synapses is the precise spatial registration of the nerve terminal and postsynaptic apparatus. This alignment has been long appreciated in nerve-muscle synapses (1) and has also been demonstrated in a wide range of neuronal synapses (2). Synaptic structure also is tightly regulated: a large number of the synaptic connections initially formed in both the central nervous system (CNS) and the periphery are pruned by the process of synapse elimination.

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The putative agrin receptor binds ligand in a calcium-dependent manner and aggregates during agrin-induced acetylcholine receptor clustering

Cited by 70 publications

References 40 publications

Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

Specific Agrin Isoforms Induce cAMP Response Element Binding Protein Phosphorylation in Hippocampal Neurons

Neurotrophins regulate agrin-induced postsynaptic differentiation

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