Signalling by CGRP and Adrenomedullin in the Cerebellum and Other Systems

The best characterised signalling pathway activated by both CGRP and adrenomedullin is stimulation of adenylate cyclase via Gs. However, it is clear that in some circumstances the peptides can activate other signal transduction pathways, e.g., increases in intracellular calcium. Many of these signalling pathways can be observed in cultured cells but it is important also to examine isolated tissues to discover the full repertoire of transduction events. In the rat cerebellum there are receptors that respond to both CGRP and adrenomedullin. These seem to be located postsynaptically on Parallel Fibre nerve terminals and modulate transmission to Purkinje cells. Adrenomedullin acts via cAMP, apparently to augment neurotransmitter release. By contrast, CGRP decreases transmitter release, via a non-cAMP mediated pathway. We are currently examining the role of NO and tyrosine kinases in the responses to these peptides.

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Src Family Kinases in the Central Nervous System：Their Emerging Role in Pathophysiology of Migraine and Neuropathic Pain

Current Neuropharmacology ◽

10.2174/1570159x18666200814180218 ◽

2020 ◽

Vol 18 ◽

Author(s):

Lingdi Nie ◽

Wen-Rui Ye ◽

Shangbin Chen ◽

Domenico Chirchiglia ◽

Minyan Wang

Keyword(s):

Neuropathic Pain ◽

Tyrosine Kinases ◽

Neurological Diseases ◽

Src Family Kinases ◽

Signalling Pathways ◽

Pain Mechanisms ◽

Promising Therapeutic Target ◽

The Central Nervous System ◽

The Relationship

: Src family kinases (SFK) are a group of non-receptor tyrosine kinases which play a pivotal role in cellular responses and oncogenesis. Accumulating evidence suggest that SFK also act as a key component in signalling pathways of the central nervous system (CNS) in both physiological and pathological conditions. Despite the crucial role of SFK in signal transduction of the CNS, the relationship between SFK and molecules implicated in pain has been relatively unexplored. This article briefly reviews the recent advances uncovering the interplay of SFK with diverse membrane proteins and intracellular proteins in the CNS and the importance of SFK in the pathophysiology of migraine and neuropathic pain. Mechanisms underlying the role of SFK in these conditions and potential clinical applications of SFK inhibitors in neurological diseases are also summarised. We propose that SFK are the convergent point of signalling pathways in migraine and neuropathic pain and may constitute a promising therapeutic target for these diseases.

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Role of intracellular Ca2+ in stimulation-induced increases in transmitter release at the frog neuromuscular junction.

The Journal of General Physiology ◽

10.1085/jgp.104.2.337 ◽

1994 ◽

Vol 104 (2) ◽

pp. 337-355 ◽

Cited By ~ 14

Author(s):

J E Zengel ◽

M A Sosa ◽

R E Poage ◽

D R Mosier

Keyword(s):

Neuromuscular Junction ◽

Transmitter Release ◽

Cyclopiazonic Acid ◽

Progressive Increase ◽

Repetitive Stimulation ◽

Frog Neuromuscular Junction ◽

Quantal Content ◽

Carbonyl Cyanide ◽

Stimulation Of

Under conditions of reduced quantal content, repetitive stimulation of a presynaptic nerve can result in a progressive increase in the amount of transmitter released by that nerve in response to stimulation. At the frog neuromuscular junction, this increase in release has been attributed to four different processes: first and second components of facilitation, augmentation, and potentiation (e.g., Zengel, J. E., and K. L. Magleby. 1982. Journal of General Physiology. 80:583-611). It has been suggested that an increased entry of Ca2+ or an accumulation of intraterminal Ca2+ may be responsible for one or more of these processes. To test this hypothesis, we have examined the role of intracellular Ca2+ in mediating changes in end-plate potential (EPP) amplitude during and after repetitive stimulation at the frog neuromuscular junction. We found that increasing the extracellular Ca2+ concentration or exposing the preparation to carbonyl cyanide m-chlorophenylhydrazone, ionomycin, or cyclopiazonic acid all led to a greater increase in EPP amplitude during conditioning trains of 10-200 impulses applied at a frequency of 20 impulses/s. These experimental manipulations, all of which have been shown to increase intracellular levels of Ca2+, appeared to act by increasing primarily the augmentation component of increased release. The results of this study are consistent with previous suggestions that the different components of increased release represent different mechanisms, and that Ca2+ may be acting at more than one site in the nerve terminal.

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Depolarization-dependent Induction of Site-specific Changes in Sialylation on N-linked Glycoproteins in Rat Nerve Terminals

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra119.001896 ◽

2020 ◽

Vol 19 (9) ◽

pp. 1418-1435

Author(s):

Inga Boll ◽

Pia Jensen ◽

Veit Schwämmle ◽

Martin R. Larsen

Keyword(s):

Synaptic Transmission ◽

Neurotransmitter Release ◽

Synaptic Proteins ◽

Nerve Terminals ◽

Membrane Glycoproteins ◽

Site Specific ◽

Specific Alteration ◽

And Function ◽

Rat Nerve ◽

Stimulation Of

Synaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show that sialylation of N-linked glycosylation is a novel potential modulator of neurotransmitter release mechanisms by investigating depolarization-dependent changes of formerly sialylated N-linked glycopeptides. We suggest that negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after 5 s depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

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Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse

Development ◽

10.1242/dev.114.1.233 ◽

1992 ◽

Vol 114 (1) ◽

pp. 233-243 ◽

Cited By ~ 41

Author(s):

K.G. Peters ◽

S. Werner ◽

G. Chen ◽

L.T. Williams

Keyword(s):

Differential Expression ◽

Gene Product ◽

Tyrosine Kinases ◽

Cultured Cells ◽

Fibroblast Growth Factors ◽

Fgf Receptor ◽

Embryonic Tissues ◽

Embryonic Skin ◽

The Individual

Fibroblast growth factors (FGFs) can influence the growth and differentiation of cultured cells derived from neuroectoderm, ectoderm or mesenchyme. The FGFs interact with a family of at least four closely related receptor tyrosine kinases that are products of individual genes. To investigate the role of FGFs in the growth and differentiation of embryonic tissues and to determine whether the individual FGF receptor genes might have specific functions, we compared the localization of mRNA for two FGF receptor genes, FGFR1 (the flg gene product) and FGFR2 (the bek gene product), during limb formation and organogenesis in mouse embryos (E9.5-E16.5). Although the two genes were coexpressed in some tissues, the differential expression of FGFR1 and FGFR2 in most embryonic tissues was striking. FGFR1 was expressed diffusely in mesenchyme of limb buds, somites and organ rudiments. In contrast, FGFR2 was expressed predominantly in the epithelial cells of embryonic skin and of developing organs. The differential expression of FGFR1 and FGFR2 in mesenchyme and epithelium respectively, suggests the receptor genes are independently regulated and that they mediate different functions of FGFs during development.

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The role of membrane cholesterol in neurotransmitter release from motor nerve terminals

Doklady Biological Sciences ◽

10.1134/s0012496611030070 ◽

2011 ◽

Vol 438 (1) ◽

pp. 138-140 ◽

Cited By ~ 5

Author(s):

O. I. Tarakanova ◽

A. M. Petrov ◽

A. L. Zefirov

Keyword(s):

Neurotransmitter Release ◽

Motor Nerve ◽

Membrane Cholesterol ◽

Nerve Terminals ◽

Motor Nerve Terminals

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The role of integrins in the modulation of neurotransmitter release from motor nerve terminals by stretch and hypertonicity

Journal of Neurocytology ◽

10.1023/b:neur.0000020606.58265.b5 ◽

2003 ◽

Vol 32 (5-8) ◽

pp. 489-503 ◽

Cited By ~ 25

Author(s):

Alan D. Grinnell ◽

Bo-Ming Chen ◽

Amir Kashani ◽

Jennifer Lin ◽

Kazuhiro Suzuki ◽

...

Keyword(s):

Neurotransmitter Release ◽

Motor Nerve ◽

Nerve Terminals ◽

Motor Nerve Terminals

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Different VAMP/Synaptobrevin Complexes for Spontaneous and Evoked Transmitter Release at the Crayfish Neuromuscular Junction

Journal of Neurophysiology ◽

10.1152/jn.1998.80.6.3233 ◽

1998 ◽

Vol 80 (6) ◽

pp. 3233-3246 ◽

Cited By ~ 42

Author(s):

Shao-Ying Hua ◽

Dorota A. Raciborska ◽

William S. Trimble ◽

Milton P. Charlton

Keyword(s):

Neuromuscular Junction ◽

Transmitter Release ◽

Neurotransmitter Release ◽

Action Potentials ◽

Neuromuscular Junctions ◽

Spontaneous Release ◽

Intracellular Ca ◽

Crayfish Neuromuscular Junction ◽

Evoked Transmitter Release

Hua, Shao-Ying, Dorota A. Raciborska, William S. Trimble, and Milton P. Charlton. Different VAMP/synaptobrevin complexes for spontaneous and evoked transmitter release at the crayfish neuromuscular junction. J. Neurophysiol. 80: 3233–3246, 1998. Although vesicle-associated membrane protein (VAMP/synaptobrevin) is essential for evoked neurotransmitter release, its role in spontaneous transmitter release remains uncertain. For instance, many studies show that tetanus toxin (TeNT), which cleaves VAMP, blocks evoked transmitter release but leaves some spontaneous transmitter release. We used recombinant tetanus and botulinum neurotoxin catalytic light chains (TeNT-LC, BoNT/B-LC, and BoNT/D-LC) to examine the role of VAMP in spontaneous transmitter release at neuromuscular junctions (nmj) of crayfish. Injection of TeNT-LC into presynaptic axons removed most of the VAMP immunoreactivity and blocked evoked transmitter release without affecting nerve action potentials or Ca2+ influx. The frequency of spontaneous transmitter release was little affected by the TeNT-LC when the evoked transmitter release had been blocked by >95%. The spontaneous transmitter release left after TeNT-LC treatment was insensitive to increases in intracellular Ca2+. BoNT/B-LC, which cleaves VAMP at the same site as TeNT-LC but uses a different binding site, also blocked evoked release but had minimal effect on spontaneous release. However, BoNT/D-LC, which cleaves VAMP at a different site from the other two toxins but binds to the same position on VAMP as TeNT, blocked both evoked and spontaneous transmitter release at similar rates. The data indicate that different VAMP complexes are employed for evoked and spontaneous transmitter release; the VAMP used in spontaneous release is not readily cleaved by TeNT or BoNT/B. Because the exocytosis that occurs after the action of TeNT cannot be increased by increased intracellular Ca2+, the final steps in neurotransmitter release are Ca2+ independent.

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