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Molecular Neurobiology Jul 2023The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal... (Review)
Review
The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal muscle fiber, leading to muscle contraction. Typically, the NMJ is a tripartite synapse comprising (a) a presynaptic region represented by the motor nerve ending, (b) a postsynaptic skeletal motor endplate area, and (c) perisynaptic Schwann cells (PSCs) that shield the motor nerve terminal. Increasing evidence points towards the role of PSCs in the maintenance and control of neuromuscular integrity, transmission, and plasticity. Acetylcholine (ACh) is the main neurotransmitter at the vertebrate skeletal NMJ, and its role is fine-tuned by co-released purinergic neuromodulators, like adenosine 5'-triphosphate (ATP) and its metabolite adenosine (ADO). Adenine nucleotides modulate transmitter release and expression of postsynaptic ACh receptors at motor synapses via the activation of P2Y and P2X receptors. Endogenously generated ADO modulates ACh release by acting via co-localised inhibitory A and facilitatory A receptors on motor nerve terminals, whose tonic activation depends on the neuronal firing pattern and their interplay with cholinergic receptors and neuropeptides. Thus, the concerted action of adenine nucleotides, ADO, and ACh/neuropeptide co-transmitters is paramount to adapting the neuromuscular transmission to the working load under pathological conditions, like Myasthenia gravis. Unravelling these functional complexities prompted us to review our knowledge about the way purines orchestrate neuromuscular transmission and plasticity in light of the tripartite synapse concept, emphasising the often-forgotten role of PSCs in this context.
Topics: Synapses; Neuromuscular Junction; Adenosine; Adenosine Triphosphate; Motor Neurons; Acetylcholine
PubMed: 37016047
DOI: 10.1007/s12035-023-03317-8 -
Advanced Biology Sep 2022Tumor cells modulate and are modulated by their microenvironments, which include the nervous system. Accumulating evidence links the overexpression and activity of... (Review)
Review
Tumor cells modulate and are modulated by their microenvironments, which include the nervous system. Accumulating evidence links the overexpression and activity of nicotinic and muscarinic cholinergic receptor subtypes to tumorigenesis in breast, ovarian, prostate, gastric, pancreatic, and head and neck cancers. Nicotinic and muscarinic receptors have downstream factors are associated with angiogenesis, cell proliferation and migration, antiapoptotic signaling, and survival. Clinical trials analyzing the efficacy of various therapies targeting cholinergic signaling or downstream pathways of acetylcholine have shed promising light on novel cancer therapeutics. Although the evidence for cholinergic signaling involvement in tumor development is substantial, a more detailed understanding of the acetylcholine-induced mechanisms of tumorigenesis remains to be unlocked. Such an understanding would enable the development of clinical applications ranging from the identification of novel biomarkers to the utilization of existing drugs to modulate cholinergic signaling to the development of novel cancer therapies, as discussed in this review.
Topics: Acetylcholine; Carcinogenesis; Cholinergic Agents; Humans; Neoplasms; Nicotine; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Nicotinic; Tumor Microenvironment
PubMed: 35858206
DOI: 10.1002/adbi.202200053 -
Frontiers in Neural Circuits 2023Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and...
Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and basal forebrain, and hippocampal-projecting neurons of the medial septum. The co-release of the functionally antagonistic neurotransmitters GABA and acetylcholine (ACh) greatly expands the possible functional effects of cholinergic neurons and provides an additional exogenous source of inhibition to the cortex. Transgene expression suggests that nearly all forebrain cholinergic neurons in mice at some point in development express , which encodes the vesicular GABA transporter (VGAT). To determine the degree of co-expression of GABA and Ach handling proteins, we measured expression in adult mice of , and (which encode GAD67 and GAD65, respectively, the GABA synthetic enzymes) in cholinergic neurons using fluorescent hybridization. We found that only a subset of cholinergic neurons express the necessary machinery for GABA release at a single time in adult mice. This suggests that GABA co-release from cholinergic neurons is dynamic and potentially developmentally regulated. By measuring expression of , , and in the basal forebrain and medial septum in mice from post-natal day 0 to 28, we noted abundant yet variable expressions of GABAergic markers across early development, which are subsequently downregulated in adulthood. This is in contrast with the forebrain-projecting pedunculopontine nucleus, which showed no evidence of co-expression of GABAergic genes. These results suggest that expression of GABA signaling machinery in the cortically-projecting cholinergic system peaks during early development before settling at a non-zero level that is maintained through adulthood.
Topics: Mice; Animals; Acetylcholine; In Situ Hybridization, Fluorescence; gamma-Aminobutyric Acid; Cholinergic Neurons; Cerebral Cortex; Gene Expression; Choline O-Acetyltransferase
PubMed: 37035505
DOI: 10.3389/fncir.2023.1125071 -
Current Pharmaceutical Design 2022
Topics: Acetylcholine; Calcium; Humans; Ryanodine Receptor Calcium Release Channel
PubMed: 35043758
DOI: 10.2174/138161282801211223123314 -
Current Protocols Feb 2023The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline...
The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline esters. The breakdown of acetylcholine by AChE terminates synaptic transmission and regulates neuromuscular communication. AChE inhibition is a common mode of action of various insecticides, such as carbamates and organophosphorus pesticides. Freshwater planarians, especially the species Dugesia japonica, have been shown to possess AChE activity and to be a suitable alternative model for studying the effects of pesticides in vivo. AChE activity can be quantified in homogenates using the Ellman assay. However, this biochemical assay requires specialized equipment and large numbers of planarians. Here, we present a protocol for visualizing AChE activity in individual planarians. Activity staining can be completed in several hours and can be executed using standard laboratory equipment (a fume hood, nutator, and light microscope with imaging capability). We describe the steps for preparing the reagents, and the staining and imaging of the planarians. Planarians are treated with 10% acetic acid and fixed with 4% paraformaldehyde and then incubated in a staining solution containing the substrate acetylthiocholine. After incubation in the staining solution for 3.5 hr on a nutator at 4°C, or stationary on ice, planarians are washed and mounted for imaging. Using exposure to an organophosphorus pesticide as an example, we show how AChE inhibition leads to a loss of staining. Thus, this simple method can be used to qualitatively evaluate AChE inhibition due to chemical exposure or RNA interference, providing a new tool for mechanistic studies of effects on the cholinergic system. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Preparing the staining solution Basic Protocol 2: Fixing, staining, and imaging whole-mount planarian specimens for visualization of acetylcholinesterase activity.
Topics: Animals; Acetylcholinesterase; Planarians; Organophosphorus Compounds; Pesticides; Acetylcholine; Fresh Water
PubMed: 36799654
DOI: 10.1002/cpz1.674 -
Analytical Biochemistry Nov 2021Acetylcholine (ACh), the major neurotransmitter secreted by cholinergic neurons, is widely found in the peripheral and central nervous systems, and its main function is... (Review)
Review
Acetylcholine (ACh), the major neurotransmitter secreted by cholinergic neurons, is widely found in the peripheral and central nervous systems, and its main function is to complete the transmission of neural signals. When cholinergic neurons are impaired, the synthesis and decomposition of ACh are abnormal and the neural signalling transition is blocked. To some extent, the concentration changes of ACh reflects the occurrence and development of many kinds of nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Myasthenia gravis and so on. Thus, researches of the physiological and pathological roles and the tracking of the concentration changes of ACh in vivo are significant to the prevention and treatment of these diseases. In the paper, the pathophysiological functions and the comprehensive research progress on detection methods of ACh are summarized. Specifically, the latest research and related applications of the optical and electrochemical biosensors are described, and the future development directions and challenges are prospected, which provides a reference for the detection and applications of ACh.
Topics: Acetylcholine; Animals; Humans
PubMed: 34534543
DOI: 10.1016/j.ab.2021.114381 -
Proceedings of the National Academy of... Jul 2023The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural...
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
Topics: Cholinergic Agents; Acetylcholine; Prosencephalon; Cholinergic Neurons; gamma-Aminobutyric Acid; Logic
PubMed: 37399414
DOI: 10.1073/pnas.2218830120 -
Optics Letters Apr 2023This paper presents a U-fiber-based biosensor to achieve temperature-compensated acetylcholine-specific measurement. The surface plasmon resonance (SPR) and multimode...
This paper presents a U-fiber-based biosensor to achieve temperature-compensated acetylcholine-specific measurement. The surface plasmon resonance (SPR) and multimode interference (MMI) effects are simultaneously realized in a U-shaped fiber structure for the first time, to the best of our knowledge. The experimental results show refractive index (RI) sensitivities of 3042 and 2958 nm/RIU and temperature sensitivities of -0.47 and -0.40 nm/°C for the MMI and SPR, which are greatly improved compared with the traditional structure. Simultaneously, a sensitivity matrix for detecting two parameters is introduced to solve the problem of temperature interference of biosensors based on RI changes. Label-free detection of acetylcholine (ACh) was achieved by immobilizing acetylcholinesterase (AChE) on optical fibers. The experimental results show that the sensor can realize the specific detection of acetylcholine and has good stability and selectivity, and the detection limit of the sensor is 30 nM. The sensor has the advantages of simple structure, high sensitivity, convenient operation, direct insertion into small spaces, temperature compensation, etc., which provide an important supplement to traditional fiber-optic SPR biosensors.
Topics: Acetylcholine; Temperature; Acetylcholinesterase; Biosensing Techniques; Surface Plasmon Resonance
PubMed: 37058661
DOI: 10.1364/OL.486504 -
Progress in Biophysics and Molecular... Jul 2021It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its... (Review)
Review
It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its structural homolog, butyrylcholinesterase, it is widely distributed both within and outside the nervous system, and, in many cases, the role of both enzymes remains obscure. The transient appearance of the cholinesterases in embryonic tissues is especially enigmatic. The two enzymes' extra-synaptic roles, which are known as 'non-classical' roles, are the topic of this review. Strong evidence has been presented that AChE and BChE play morphogenetic roles in a variety of eukaryotic systems, and they do so either by acting as adhesion proteins, or as trophic factors. As trophic factors, one mode of action is to directly regulate morphogenesis, such as neurite outgrowth, by poorly understood mechanisms. The other mode is by regulating levels of acetylcholine, which acts as the direct trophic factor. Alternate substrates have been sought for the cholinesterases. Quite recently, it was shown that levels of the aggression hormone, ghrelin, which also controls appetite, are regulated by butyrylcholinesterase. The rapid hydrolysis of acetylcholine by acetylcholinesterase generates high local proton concentrations. The possible biophysical and biological consequences of this effect are discussed. The biological significance of the acetylcholinesterases secreted by parasitic nematodes is reviewed, and, finally, the involvement of acetylcholinesterase in apoptosis is considered.
Topics: Acetylcholine; Acetylcholinesterase; Butyrylcholinesterase; Morphogenesis; Synapses
PubMed: 33307019
DOI: 10.1016/j.pbiomolbio.2020.12.001 -
Preface: Cholinergic mechanisms: This is the Preface for the special issue "Cholinergic Mechanisms".Journal of Neurochemistry Sep 2021This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover...
This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems.
Topics: Acetylcholine; Animals; Brain; Cholinergic Agents; Cholinergic Neurons; Humans; Peripheral Nervous System; Synaptic Transmission
PubMed: 34458988
DOI: 10.1111/jnc.15480