Neurogenic calcitonin gene-related peptide: a neurotrophic factor in the maintenance of acetylcholinesterase molecular forms in adult skeletal muscles

Fernández, Hugo L.; Ross, George; Nadelhaft, Irving

doi:10.1016/s0006-8993(99)01891-0

Cited by 31 publications

(26 citation statements)

References 49 publications

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“…This observation suggests that cAMP also affects expression of the noncatalytic collagenic tail subunit, ColQ. These observations are consistent with observations from several groups on the effects of CGRP on AChE in mammalian skeletal muscle, both in vivo (12)(13)(14) and in vitro (46 -48) where down-regulation of the enzyme has been documented. In contrast, one laboratory has shown that CGRP and increasing cAMP levels had no effect on the expression of chicken AChE activity, whereas it increased the expression of AChE mRNA and protein, representing an inactive form of the enzyme (49,50).…”

Section: Figsupporting

confidence: 90%

“…[1][2][3][4], where it is released upon stimulation (5). In skeletal muscle, CGRP has been shown to potentiate muscle contraction (6), increase the rate of acetylcholine receptor (AChR) desensitization (7)(8)(9)(10), increase the numbers of AChR (11), decrease the levels of acetylcholinesterase (AChE) (12)(13)(14), and locally increase the rate of blood flow following muscle contraction (15)(16)(17). Although the presence of CGRP in nerve terminals at the neuromuscular junction has been well documented (18 -21), the localization of CGRP receptors at the synapse has been more difficult to demonstrate because the only available probe was the receptor ligand itself, CGRP.…”

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confidence: 99%

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Localization of the Calcitonin Gene-related Peptide Receptor Complex at the Vertebrate Neuromuscular Junction and Its Role in Regulating Acetylcholinesterase Expression

Rossi¹,

Dickerson

Rotundo

2003

Journal of Biological Chemistry

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The calcitonin gene-related peptide (CGRP) is released by motor neurons where it exerts both short and long term effects on skeletal muscle fibers. In addition, sensory neurons release CGRP on the surrounding vasculature where it is in part responsible for local vasodilation following muscle contraction. Although CGRPbinding sites have been demonstrated in whole muscle tissue, the type of CGRP receptor and its associated proteins or its cellular localization within the tissue have not been described. Here we show that the CGRPbinding protein referred to as the calcitonin receptorlike receptor is highly concentrated at the avian neuromuscular junction together with its two accessory proteins, receptor activity modifying protein 1 and CGRP-receptor component protein, required for ligand specificity and signal transduction. Using tissue-cultured skeletal muscle we show that CGRP stimulates an increase in intracellular cAMP that in turn initiates down-regulation of acetylcholinesterase expression at the transcriptional level, and, more specifically, inhibits expression of the synaptically localized collagen-tailed form of the enzyme. Together, these studies suggest a specific role for CGRP released by spinal cord motoneurons in modulating synaptic transmission at the neuromuscular junction by locally inhibiting the expression of acetylcholinesterase, the enzyme responsible for terminating acetylcholine neurotransmission.The calcitonin gene-related peptide (CGRP) 1 is a 37-amino acid neuropeptide expressed in a wide variety of neurons in the central and peripheral nervous systems, including motoneurons (reviewed in Refs. 1-4), where it is released upon stimulation (5). In skeletal muscle, CGRP has been shown to potentiate muscle contraction (6), increase the rate of acetylcholine receptor (AChR) desensitization (7-10), increase the numbers of AChR (11), decrease the levels of acetylcholinesterase (AChE) (12)(13)(14), and locally increase the rate of blood flow following muscle contraction (15)(16)(17). Although the presence of CGRP in nerve terminals at the neuromuscular junction has been well documented (18 -21), the localization of CGRP receptors at the synapse has been more difficult to demonstrate because the only available probe was the receptor ligand itself, CGRP. Using 125 I-CGRP as a probe, high affinity CGRP receptors were shown to be expressed on the surfaces of tissuecultured myotubes (22) and present on whole muscle membranes isolated from embryonic or newly hatched chicks (23); however, the latter studies could not differentiate between CGRP receptors on skeletal muscle versus those on the surrounding vasculature. In one autoradiographic study (24), a correlation between 125 I-CGRP and AChE histochemical staining was observed in low power photomicrographs of rat bulbocavernosus muscle, suggesting an accumulation of CGRP receptors at sites of nerve-muscle contact. However, in these studies it was not possible to differentiate between CGRP receptors located in blood vessels or Schwann cells and those on m...

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Section: Figsupporting

confidence: 90%

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confidence: 99%

Localization of the Calcitonin Gene-related Peptide Receptor Complex at the Vertebrate Neuromuscular Junction and Its Role in Regulating Acetylcholinesterase Expression

Rossi¹,

Dickerson

Rotundo

2003

Journal of Biological Chemistry

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“…Of these, CGRP is of special interest because this 37‐amino acid neuropeptide has been found in large dense‐core vesicles (LDCVs) in mammalian motor nerve terminals (Csillik et al., 1993; Matteoli et al., 1988) and is reported to be released as a co‐transmitter in response to sustained depolarization or intense nerve stimulation (Sakaguchi, Inaishi, Kashihara, & Kuno, 1991; Sala, Andreose, Fumagalli, & Lømo, 1995; Uchida et al., 1990) providing the wide spectrum of acute and neurotrophic influences (Buffelli, Pasino, & Cangiano, 2001; Changeux, Duclert, & Sekine, 1992; Correia‐de‐Sá & Ribeiro, 1994; Fernandez, Ross, & Nadelhaft, 1999; Kimura, Okazaki, & Nojima, 1997; Machado et al., 2016; Rossi, Dickerson, & Rotundo, 2003; Salim, Dezaki, Tsuneki, Abdel‐Zaher, & Kimura, 1998). Possible release of endogenous CGRP in response to ryanodine application at resting motor synapses and acute physiological consequences of this release on quantal ACh secretion have not been described yet.…”

Section: Introductionmentioning

confidence: 99%

Ryanodine‐ and CaMKII‐dependent release of endogenous CGRP induces an increase in acetylcholine quantal size in neuromuscular junctions of mice

Gaydukov

Балезина

2018

Brain and Behavior

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ObjectiveThe aim of this study was to identify the mechanism responsible for an increase in miniature endplate potentials (MEPPs) amplitude, induced by ryanodine as an agonist of ryanodine receptors in mouse motor nerve terminals.MethodsUsing intracellular microelectrode recordings of MEPPs and evoked endplate potentials (EPPs), the changes in spontaneous and evoked acetylcholine release in motor synapses of mouse diaphragm neuromuscular preparations were studied.ResultsRyanodine (0.1 μM) increased both the amplitudes of MEPPs and EPPs to a similar extent (up to 130% compared to control). The ryanodine effect was prevented by blockage of receptors of calcitonin gene‐related peptide (CGRP) by a truncated peptide CGRP 8‐37. Endogenous CGRP is stored in large dense‐core vesicles in motor nerve terminals and may be released as a co‐transmitter. The ryanodine‐induced increase in MEPPs amplitude may be fully prevented by inhibition of vesicular acetylcholine transporter by vesamicol or by blocking the activity of protein kinase A with H‐89, suggesting that endogenous CGRP is released in response to the activation of ryanodine receptors. Activation of CGRP receptors can, in turn, upregulate the loading of acetylcholine into synaptic vesicles, which will increase the quantal size. This new feature of endogenous CGRP activity looks similar to recently described action of exogenous CGRP in motor synapses of mice. The ryanodine effect was prevented by inhibitors of Ca/Calmodulin‐dependent kinase II (CaMKII) KN‐62 or KN‐93. Inhibition of CaMKII did not prevent the increase in MEPPs amplitude, which was caused by exogenous CGRP.ConclusionsWe propose that the activity of presynaptic CaMKII is necessary for the ryanodine‐stimulated release of endogenous CGRP from motor nerve terminals, but CaMKII does not participate in signaling downstream the activation of CGRP‐receptors followed by quantal size increase.

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“…9,10 CGRP is widely expressed in both central and peripheral nervous systems. 11 In the periphery, the expression is in both unmyelinated C-fibers and thinly myelinated A␦ fibers innervating almost all organs including epidermis, 12 sweat glands, 13 skeletal muscles, 14 airway, and enteric system, in addition to the vasculatures. Furthermore, CGRP-positive vagal nerve fibers have also been identified.…”

Section: Introductionmentioning

confidence: 99%

CGRP Receptor Antagonism and Migraine

Edvinsson

2010

Neurotherapeutics

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Summary: Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. ␣CGRP is prominently localized in primary spinal afferent C and A⌬ fibers of sensory ganglia, and ␤CGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

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Neurogenic calcitonin gene-related peptide: a neurotrophic factor in the maintenance of acetylcholinesterase molecular forms in adult skeletal muscles

Cited by 31 publications

References 49 publications

Localization of the Calcitonin Gene-related Peptide Receptor Complex at the Vertebrate Neuromuscular Junction and Its Role in Regulating Acetylcholinesterase Expression

Localization of the Calcitonin Gene-related Peptide Receptor Complex at the Vertebrate Neuromuscular Junction and Its Role in Regulating Acetylcholinesterase Expression

Ryanodine‐ and CaMKII‐dependent release of endogenous CGRP induces an increase in acetylcholine quantal size in neuromuscular junctions of mice

CGRP Receptor Antagonism and Migraine

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