Neurotrophin and Trk-mediated Signaling in the Neuromuscular System

Pitts, Elizabeth Vernon; Potluri, S.; Hess, Darren; Balice-Gordon, Rita J.

doi:10.1097/00004311-200604420-00004

Cited by 78 publications

(72 citation statements)

References 336 publications

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“…The expression of neurotrophins and their receptors in muscle and nerve tissues in both development and adulthood has been shown previously (Funakoshi et al, 1993(Funakoshi et al, , 1995Griesbeck et al, 1995;Gonzalez et al, 1999;Ip et al, 2001;Nagano and Suzuki, 2003;Pitts et al, 2006). Here, we show the presence of these molecules in the nerve terminals at adult NMJs (see also Garcia et al, 2010c).…”

Section: Discussionsupporting

confidence: 82%

“…At the presynaptic level, membrane receptors for these mediators control the functional conditions of transmitter release in response to variable activity demands. In the neuromuscular synapse, muscarinic acetylcholine autoreceptors (mAChRs) (Caulfield, 1993;Slutsky et al, 1999;Minic et al, 2002;Santafé et al, 2003Santafé et al, , 2004Garcia et al, 2005), adenosine receptors (Song et al, 2000), neurotrophin receptors (Bibel and Barde, 2000;Roux and Barker, 2002;Pitts et al, 2006), and receptors for other trophic factors cooperate to produce synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

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The Interaction between Tropomyosin-Related Kinase B Receptors and Presynaptic Muscarinic Receptors Modulates Transmitter Release in Adult Rodent Motor Nerve Terminals

García

Tomàs²,

Santafé³

et al. 2010

J. Neurosci.

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The neurotrophin brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and the receptors tropomyosin-related kinase B (trkB) and p75NTR are present in the nerve terminals on the neuromuscular junctions (NMJs) of the levator auris longus muscle of the adult mouse. Exogenously added BDNF or NT-4 increased evoked ACh release after 3 h. This presynaptic effect (the size of the spontaneous potentials is not affected) is specific because it is not produced by neurotrophin-3 (NT-3) and is prevented by preincubation with trkB-IgG chimera or by pharmacological block of trkB [K-252a (C 27 muscarinic acetylcholine autoreceptors (mAChRs) because it is prevented by atropine, pirenzepine and methoctramine. We found that K-252a incubation reduces ACh release (ϳ50%) in a short time (1 h), but the p75 NTR signaling inhibitor Pep5 does not have this effect. The specificity of the K-252a blocking effect on trkB was confirmed with the anti-trkB antibody 47/trkB, which reduces evoked ACh release, like K-252a, whereas the nonpermeant tyrosine kinase blocker K-252b does not. Neither does incubation with the fusion protein trkB-IgG (to chelate endogenous BDNF/NT-4), anti-BDNF or anti-NT-4 change ACh release. Thus, the trkB receptor normally seems to be coupled to ACh release when there is no short-term local effect of neurotrophins at the NMJ. The normal function of the mAChR mechanism is a permissive prerequisite for the trkB pathway to couple to ACh release. Reciprocally, the normal function of trkB modulates M 1 -and M 2 -subtype muscarinic pathways.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

The Interaction between Tropomyosin-Related Kinase B Receptors and Presynaptic Muscarinic Receptors Modulates Transmitter Release in Adult Rodent Motor Nerve Terminals

García

Tomàs²,

Santafé³

et al. 2010

J. Neurosci.

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“…Second, it is widely accepted that motoneurons express only TrkB, but TrkC and TrkA expression is controversial. In addition, negligible levels of NGF are detectable in the neuromuscular system (46) and TrkB expression in sympathetic neurons is extremely low (47). Therefore, application of excessive BDNF, even with low affinity, can only bind to p75 NTR , triggering axonal pruning.…”

Section: Stimmentioning

confidence: 99%

Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses

Yang

et al. 2012

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

153

134

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Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activitydependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNFp75 NTR signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination. neuromuscular junction | pro-neurotrophin | synapse competition

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“…51 Regarding neurotrophins, the R26Q mutation and its effects on TrkA internalization could be of pathophysiological significance because the Trk receptor family is important for the development and maintenance of the neuromuscular junction. 52,53 …”

Section: Differential Effects Of the R26q And P28l Mutations On Egfr mentioning

confidence: 99%

Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling

Brauers

Dreier

Roos

et al. 2010

The American Journal of Pathology

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Caveolin-3 is an important scaffold protein of cholesterol-rich caveolae. Mutations of caveolin-3 cause hereditary myopathies that comprise remarkably different pathologies. Growth factor signaling plays an important role in muscle physiology; it is influenced by caveolins and cholesterol-rich rafts and might thus be affected by caveolin-3 dysfunction. Prompted by the observation of a marked chronic peripheral neuropathy in a patient suffering from rippling muscle disease due to the R26Q caveolin-3 mutation and because TrkA is expressed by neuronal cells and skeletal muscle fibers, we performed a detailed comparative study on the effect of pathogenic caveolin-3 mutants on the signaling and trafficking of the TrkA nerve growth factor receptor and, for comparison, of the epidermal growth factor receptor. We found that the R26Q mutant slightly and the P28L strongly reduced nerve growth factor signaling in TrkA-transfected cells. Surface biotinylation experiments revealed that the R26Q caveolin-3 mutation markedly reduced the internalization of TrkA, whereas the P28L did not. Moreover, P28L expression led to increased, whereas R26Q expression decreased, epidermal growth factor signaling. Taken together, we found differential effects of the R26Q and P28L caveolin-3 mutants on growth factor signaling. Our findings are of clinical interest because they might help explain the remarkable differences in the degree of muscle lesions caused by caveolin-3 mutations and also the co-occurrence of peripheral neuropathy in the R26Q caveolinopathy case presented.

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Neurotrophin and Trk-mediated Signaling in the Neuromuscular System

Cited by 78 publications

References 336 publications

The Interaction between Tropomyosin-Related Kinase B Receptors and Presynaptic Muscarinic Receptors Modulates Transmitter Release in Adult Rodent Motor Nerve Terminals

The Interaction between Tropomyosin-Related Kinase B Receptors and Presynaptic Muscarinic Receptors Modulates Transmitter Release in Adult Rodent Motor Nerve Terminals

Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses

Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling

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