Neuronal-type acetylcholine receptors and regulation of ?7 gene expression in vertebrate skeletal muscle

Romano, Suzanne J.; Pugh, Phyllis C.; McIntosh, J. Michael; Berg, Daniela

doi:10.1002/(sici)1097-4695(199701)32:1<69::aid-neu7>3.0.co;2-c

Cited by 39 publications

(15 citation statements)

References 50 publications

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“…Although this and other reports show that osteoblasts express several nAChRs subunits (37), no significant changes in bone formation were found following central IL-1 receptor silencing or stimulation of skeletal ACh levels by pyridostigmine treatment. Although low concentrations of nAChRs agonists are mitogenic to osteoblasts, this effect is reversed by higher concentrations, shown to induce osteoclast apoptosis.…”

Section: Discussioncontrasting

confidence: 91%

“…It thus appears that physiologically ACh regulates only bone resorption and that the cholinergic regulation of osteoblast number becomes effective only when ACh levels are reduced in an attempt to attenuate the noradrenegic inhibition of bone formation (4) in situations such as stress, depression, and pain disorders (38). The nAChR subunit profile demonstrated here in osteoblasts is reminiscent of previously reported expression profiles (37). Although muscarinic receptors have been recently described in human bone samples and in in vitro osteoblast models (39), we and others were unable to show significant levels of these receptors in bone cells and their conditional deletion in osteoblasts has no skeletal effects (19).…”

Section: Discussionsupporting

confidence: 71%

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Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bajayo¹,

Bar²,

Dénes

et al. 2012

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

144

162

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Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α 2 nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra Ast +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra Ast +/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.autonomic nervous system | postnatal skeletal development

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Section: Discussioncontrasting

confidence: 91%

Section: Discussionsupporting

confidence: 71%

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bajayo¹,

Bar²,

Dénes

et al. 2012

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

144

162

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“…S6) and AChRα1/AChRα7/agrin mutants fail to exhibit clustering of either AChE or MuSK. Therefore, because (α7) 5 and (α1) 2 βδγ pentamers are the only AChR complexes present in embryonic muscle (18,19), our results indicate that ACh inhibits both preand postsynaptic differentiation by a mechanism that does not involve postsynaptic receptor clusters; instead, we suggest that the inhibitory activity is likely mediated by AChRs on nerve terminals or Schwann cells.…”

Section: Loss Of Muscle Receptors Results In Increased Nerve Branchinmentioning

confidence: 73%

“…To address this issue, we studied the effect of removing exclusively muscle-derived postsynaptic AChRs on synaptic growth and differentiation. Available data show that embryonic muscle expresses two types of nicotinic AChR complexes that use AChRα1 or AChRα7 as the ligand-binding subunits (18,19), but no other nicotinic AChR complexes or muscarinic AChR subtypes are used (13,(20)(21)(22). Therefore, we analyzed mice deficient in AChRα1 and/ or AChRα7 subunits.…”

mentioning

confidence: 99%

Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

Lin²,

Yang

et al. 2010

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

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Emerging evidence suggests that the neurotransmitter acetylcholine (ACh) negatively regulates the development of the neuromuscular junction, but it is not clear if ACh exerts its effects exclusively through muscle ACh receptors (AChRs). Here, we used genetic methods to remove AChRs selectively from muscle. Similar to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs increased motor axon branching and expanded innervation territory, suggesting that ACh negatively regulates synaptic growth through postsynaptic AChRs. However, in contrast to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs in agrin-deficient mice failed to restore deficits in pre- and postsynaptic differentiation, suggesting that ACh negatively regulates synaptic differentiation through nonpostsynaptic receptors. Consistent with this idea, the ACh agonist carbachol inhibited presynaptic specialization of motorneurons in vitro. Together, these data suggest that ACh negatively regulates axon growth and presynaptic specialization at the neuromuscular junction through distinct cellular mechanisms.

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“…Considering that ␣7 nAChRs are in the evolutionary oldest family of nAChRs (Le Novere and Changeux, 1999), it is tempting to speculate that choline rather than ACh was the natural transmitter for these receptors. This is particularly relevant because ␣7 nAChRs seem to play a significant role in numerous aspects of development of cholinergic synapses both at the neuromuscular junction (Romano et al, 1997;Fischer et al, 1999) and in the nervous systems (Broide and Leslie, 1999). It is possible that during maturation of the nervous systems choline acts as the primary endogenous agonist of ␣7 nAChRs, given that expression of the ACh synthesizing enzyme choline acetyltransferase lags behind the appearance of nAChRs in developing neurons (Chiappinelli and Giacobini, 1978;Yamada et al, 1986;Aubert et al, 1996).…”

Section: Endogenous Unconventional Nachr Ligands That Modulate Recepmentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

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Neuronal-type acetylcholine receptors and regulation of ?7 gene expression in vertebrate skeletal muscle

Cited by 39 publications

References 50 publications

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

Unconventional ligands and modulators of nicotinic receptors

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