Expression and Localization of PRiMA-Linked Globular Form Acetylcholinesterase in Vertebrate Neuromuscular Junctions

Tsim, Karl Wah Keung; Leung, Ka Wing; Mok, Ka Wai; Chen, Vicky P.; Zhu, Kevin Y.; Zhu, Judy Ting Ting; Guo, Ava J.Y.; Bi, Cathy W. C.; Zheng, Yuzhong; Lau, David Tai-Wai; Xie, Heidi Qunhui; Choi, Roy Chi Yan

doi:10.1007/s12031-009-9251-2

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…That PRiMA mRNA and protein are expressed both in the spinal cord (motoneuron) and in muscle might indicate that AChE-PRiMA contributes quantitatively to AChE expression at the NMJ (Tsim et al, 2010), however, we have shown in several ways that AChE-PRiMA localization at the NMJ is minimal. Having established the very small amounts of AChE-PRiMA found in the neuromuscular junction, one must still account for the large amount of AChE-PRiMA that is found in muscle.…”

Section: Discussionmentioning

confidence: 59%

Distinct localization of collagen Q and PRiMA forms of acetylcholinesterase at the neuromuscular junction

Bernard

Girard

Hrabovská

et al. 2011

Molecular and Cellular Neuroscience

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Acetylcholinesterase (AChE) terminates the action of acetylcholine at cholinergic synapses thereby preventing rebinding of acetylcholine to nicotinic post-synaptic receptors at the neuromuscular junction. Here we show that AChE is not localized close to these receptors on the post-synaptic surface, but is instead clustered along the presynaptic membrane and deep in the post-synaptic folds. Because AChE is anchored by ColQ in the basal lamina and is linked to the plasma membrane by a transmembrane subunit (PRiMA), we used a genetic approach to evaluate the respective contribution of each anchoring oligomer. By visualization and quantification of AChE in mouse strains devoid of ColQ, PRiMA or AChE, specifically in the muscle, we found that along the nerve terminus, the vast majority of AChE is anchored by ColQ that is only produced by the muscle, whereas very minor amounts of AChE are anchored by PRiMA that is produced by motoneurons. In its synaptic location, AChE is therefore positioned to scavenge ACh that effluxes from the nerve by non-quantal release. AChE-PRiMA, produced by the muscle, is diffusely distributed along the muscle in extra-junctional regions.

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Section: Discussionmentioning

confidence: 59%

Distinct localization of collagen Q and PRiMA forms of acetylcholinesterase at the neuromuscular junction

Bernard

Girard

Hrabovská

et al. 2011

Molecular and Cellular Neuroscience

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“…This region displays a high level of similarity to acetylcholinesterase, hence its name. Acetylcholinesterase catalyzes the degradation of acetylcholine in the regulation of neurotransmission [46]. Blastall analyses of the ChEL domain identified 992 proteins displaying sequence similarity to this domain: 30 thyroglobulin proteins, 598 esterases (either carboxylesterases (n = 205) or cholinesterases (n = 150)) and 35 neuroligins.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of the human thyroglobulin regions

et al. 2012

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Thyroglobulin is a large protein present in all vertebrates. It is synthesized in the thyrocytes and exported to lumen of the thyroid follicle, where its tyrosine residues are iodinated . The iodinated thyroglobulin is reintegrated into the cell and processed (cleaved to free its two extremities) for thyroid hormone synthesis. Thyroglobulin sequence analysis has identified four regions of the molecule: Tg1, Tg2, Tg3 and ChEL. Structural abnormalities and mutations result in different pathological consequences, depending on the thyroglobulin region affected. We carried out a bioinformatic analysis of thyroglobulin, determining the origin and the function of each region. Our results suggest that the Tg1 region acts as a binding protein on the apical membrane, the Tg2 region is involved in protein adhesion and the Tg3 region is involved in determining the three-dimensional structure of the protein. The ChEL domain is involved in thyroglobulin transport, dimerization and adhesion. The presence of repetitive domains in the Tg1, Tg2 and Tg3 regions suggests that these domains may have arisen through duplication.

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“…In addition, the different locations observed may reflect distinct types of AChE isoforms (e.g., A-form vs. globular hydrophobic G4). It is well established that AChE at NMJs can be produced by both muscle (Hall and Kelly, 1971 ; Vigny et al, 1976 ; Anglister and McMahan, 1985 ; Lømo et al, 1985 ; Rotundo et al, 2005 ) and nerve (Anglister, 1991 ; Jiang et al, 2003 ; Mis et al, 2005 ; Tsim et al, 2010 ). Synaptic AChE is composed primarily of the large asymmetric collagen-tailed isoforms (mainly A 12 -AChE; reviewed in Legay, 2000 ; Massoulié, 2002 ; Rotundo, 2003 ; Massoulié and Millard, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that much of the synaptic AChE at the NMJ is associated with the BL (McMahan et al, 1978 ; Anglister et al, 1994a ; for review see Massoulié and Millard, 2009 ), and is composed primarily of the asymmetric collagen-tailed AChE isoforms (A-AChE; for reviews see Legay, 2000 ; Massoulié, 2002 ; Rotundo, 2003 ; Massoulié and Millard, 2009 ). However, at least some of the synaptic AChE at the NMJs, and almost all the AChE at cholinergic synapses in the CNS, consists of a hydrophobic membrane-bound globular tetramer (G 4 -AChE; e.g., Fernandez et al, 1996 ; Perrier et al, 2002 ; Tsim et al, 2010 ), which is elevated by exercise (e.g., Gisiger et al, 1994 ; Blotnick and Anglister, 2016 ). Moreover, while part of the synaptic enzyme at the NMJ is provided by the muscle (Hall and Kelly, 1971 ; Vigny et al, 1976 ; Lømo et al, 1985 ; Anglister et al, 1994a ), accumulated evidence indicates anterograde axonal transport of AChE (Di Giamberardino and Couraud, 1978 ), as well as a direct neuronal contribution (Anglister, 1991 ; Jiang et al, 2003 ; Mis et al, 2005 ; Tsim et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, at least some of the synaptic AChE at the NMJs, and almost all the AChE at cholinergic synapses in the CNS, consists of a hydrophobic membrane-bound globular tetramer (G 4 -AChE; e.g., Fernandez et al, 1996 ; Perrier et al, 2002 ; Tsim et al, 2010 ), which is elevated by exercise (e.g., Gisiger et al, 1994 ; Blotnick and Anglister, 2016 ). Moreover, while part of the synaptic enzyme at the NMJ is provided by the muscle (Hall and Kelly, 1971 ; Vigny et al, 1976 ; Lømo et al, 1985 ; Anglister et al, 1994a ), accumulated evidence indicates anterograde axonal transport of AChE (Di Giamberardino and Couraud, 1978 ), as well as a direct neuronal contribution (Anglister, 1991 ; Jiang et al, 2003 ; Mis et al, 2005 ; Tsim et al, 2010 ). The differences in AChE origin and isoform composition could result in differential localization within the synaptic cleft.…”

Section: Introductionmentioning

confidence: 99%

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Fine Localization of Acetylcholinesterase in the Synaptic Cleft of the Vertebrate Neuromuscular Junction

Blotnick-Rubin¹,

Anglister²

2018

Front. Mol. Neurosci.

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Acetylcholinesterase (AChE) is concentrated at cholinergic synapses, where it is a major factor in controlling the duration of transmitter action. The concentration and localization of AChE within the synaptic cleft are in keeping with the functional requirements of the particular type of synapse. The densities of synaptic AChE at various neuromuscular junctions (NMJs) had been evaluated by quantitative EM-autoradiography using radiolabeled probes. Yet, fundamental issues concerning the precise distribution and location of the enzyme in the cleft remained open: whether and to what extent synaptic AChE is associated with pre- or postsynaptic membranes, or with synaptic basal lamina (BL), and whether it occurs only in the primary cleft (PC) or also in postjunctional folds (PJFs). Nanogold-conjugates of fasciculin, an anticholinesterase polypeptide toxin, were prepared and used to label AChE at NMJs of mouse and frog muscles. Selective intense labeling was obtained at the NMJs, with gold-labeled AChE sites distributed over the BL in the PC and the PJFs. Quantitative analysis demonstrated that AChE sites are almost exclusively located on the BL rather than on pre- or postsynaptic membranes and are distributed in the PC and down the PJFs, with a defined pattern. This localization pattern of AChE is suggested to ensure full hydrolysis of acetylcholine (ACh) bouncing off receptors, thus eliminating its unnecessary detrimental reattachment.

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Expression and Localization of PRiMA-Linked Globular Form Acetylcholinesterase in Vertebrate Neuromuscular Junctions

Cited by 9 publications

References 23 publications

Distinct localization of collagen Q and PRiMA forms of acetylcholinesterase at the neuromuscular junction

Distinct localization of collagen Q and PRiMA forms of acetylcholinesterase at the neuromuscular junction

Phylogenetic analysis of the human thyroglobulin regions

Fine Localization of Acetylcholinesterase in the Synaptic Cleft of the Vertebrate Neuromuscular Junction

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