-
The Journal of Neuroscience : the... Mar 2021Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional... (Review)
Review
Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. and experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter sensors in expanding our knowledge of various behaviors and diseases, including Alzheimer's disease, sleeping disorders, tumorigenesis, and many others.
Topics: Acetylcholine; Animals; Biogenic Monoamines; Cell Communication; Humans; Neurons; Neurotransmitter Agents; Synapses; Synaptic Transmission
PubMed: 33627325
DOI: 10.1523/JNEUROSCI.1062-19.2020 -
Journal of Visualized Experiments : JoVE Apr 2022Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using...
Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using acetylcholine (ACh) spasm provocation testing. CAS can further be divided into different subtypes (e.g., focal, diffuse epicardial, or microvascular spasm), each with different pathophysiological mechanisms that may require tailored drug treatment. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. In order to assess on a per-patient level whether nitroglycerine (NTG) can prevent inducible spasm, the vasospastic ACh dose can be readministered after NTG administration as part of the spasm provocation test. The preventive effect of NTG is assessed by evaluating improvements in the severity of induced symptoms, ischemic ECG changes, and by reassessing the site and mode of spasm on angiography. This technique can therefore be used to assess the nitrate responsiveness on a per-patient level and unmask co-existing microvascular spasm in patients with epicardial spasm that is prevented with NTG. The NTG rechallenge, therefore, allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders.
Topics: Acetylcholine; Coronary Angiography; Coronary Vasospasm; Coronary Vessels; Humans; Spasm
PubMed: 35435907
DOI: 10.3791/62406 -
International Journal of Molecular... Dec 2021Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the... (Review)
Review
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.
Topics: Acetylcholine; Bile Acids and Salts; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Pancreatic Neoplasms; Receptors, Muscarinic; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment
PubMed: 34884958
DOI: 10.3390/ijms222313153 -
International Journal For Parasitology.... Apr 2022Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In... (Review)
Review
Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.
Topics: Acetylcholine; Animals; Anthelmintics; Nematoda; Receptors, GABA; Receptors, Nicotinic
PubMed: 35149380
DOI: 10.1016/j.ijpddr.2021.12.001 -
Journal of Neurophysiology May 2023Many behaviors and types of information storage are mediated by lengthy changes in neuronal activity. In bag cell neurons of the hermaphroditic sea snail , a transient...
Many behaviors and types of information storage are mediated by lengthy changes in neuronal activity. In bag cell neurons of the hermaphroditic sea snail , a transient cholinergic synaptic input triggers an ∼30-min afterdischarge. This causes these neuroendocrine cells to release egg laying hormone and elicit reproductive behavior. When acetylcholine is pressure-ejected onto a current-clamped bag cell neuron, the evoked depolarization is far longer than the current evoked by acetylcholine under voltage clamp, suggesting recruitment of another conductance. Our earlier studies found bag cell neurons to display a voltage-dependent persistent Ca current. Hence, we hypothesized that this current is activated by the acetylcholine-induced depolarization and sought a selective Ca current blocker. Rapid Ca current evoked by 200-ms depolarizing steps in voltage-clamped cultured bag cell neurons demonstrated a concentration-dependent sensitivity to Ni, Co, Zn, and verapamil but not Cd or ω-conotoxin GIVa. Leak subtraction of Ca current evoked by 10-s depolarizing steps using the IC (concentration required to eliminate maximal current) of Ni, Co, Zn, or verapamil revealed persistent Ca current, demonstrating persistent current block. Only Co and Zn did not suppress the acetylcholine-induced current, although Zn appeared to impact additional channels. When Co was applied during an acetylcholine-induced depolarization, the amplitude was reduced; furthermore, protein kinase C activation, previously established to enhance the persistent Ca current, extended the depolarization. Therefore, the persistent Ca current sustains the acetylcholine-induced depolarization and may translate brief cholinergic input into afterdischarge initiation. This could be a general mechanism of triggering long-term change in activity with a short-lived input. Ionotropic acetylcholine receptors mediate brief synaptic communication, including in bag cell neurons of the sea snail . However, this study demonstrates that cholinergic depolarization can open a voltage-gated persistent Ca current, which extends the bag cell neuron response to acetylcholine. Bursting in these neuroendocrine cells results in hormone release and egg laying. Thus, this emphasizes the role of ionotropic signaling in reaching a depolarized level to engage Ca influx and perpetuating the activity necessary for behavior.
Topics: Animals; Aplysia; Acetylcholine; Neurons; Cholinergic Agents; Verapamil; Hormones; Calcium
PubMed: 36988203
DOI: 10.1152/jn.00429.2022 -
Trends in Neurosciences Feb 2022Cholinergic innervation of the hippocampus uses the neurotransmitter acetylcholine (ACh) to coordinate neuronal circuit activity while simultaneously influencing the... (Review)
Review
Cholinergic innervation of the hippocampus uses the neurotransmitter acetylcholine (ACh) to coordinate neuronal circuit activity while simultaneously influencing the function of non-neuronal cell types. The α7 nicotinic ACh receptor (nAChR) subtype is highly expressed throughout the hippocampus, has the highest calcium permeability compared with other subtypes of nAChRs, and is of high therapeutic interest due to its association with a variety of neurological disorders and neurodegenerative diseases. In this review, we synthesize research describing α7 nAChR properties, function, and relationship to cognitive dysfunction within the hippocampal circuit and highlight approaches to help improve therapeutic development.
Topics: Acetylcholine; Hippocampus; Humans; Neurons; Receptors, Nicotinic; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 34916082
DOI: 10.1016/j.tins.2021.11.006 -
American Journal of Physiology. Cell... Feb 2021The innate and adaptive immune systems play an important role in the development of cardiac diseases. Therefore, it has become critical to identify molecules that can... (Review)
Review
The innate and adaptive immune systems play an important role in the development of cardiac diseases. Therefore, it has become critical to identify molecules that can modulate inflammation in the injured heart. In this regard, activation of the cholinergic system in animal models of heart disease has been shown to exert protective actions that include immunomodulation of cardiac inflammation. In this mini-review, we briefly present our current understanding on the cardiac cellular sources of acetylcholine (ACh) (neuronal vs. nonneuronal), followed by a discussion on its contribution to the regulation of inflammatory cells. Although the mechanism behind ACh-mediated protection still remains to be fully elucidated, the beneficial immunomodulatory role of the cholinergic signaling emerges as a potential key regulator of cardiac inflammation.
Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Cardiotonic Agents; Heart; Heart Diseases; Humans; Inflammation; Neurons
PubMed: 33264077
DOI: 10.1152/ajpcell.00315.2020 -
Anesthesiology Apr 2021Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice...
BACKGROUND
Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice with genetic deficiency of forebrain acetylcholine show increased anesthetic sensitivity to isoflurane and ketamine and decreased gamma-frequency brain activity.
METHODS
Male adult mice with heterozygous knockdown of vesicular acetylcholine transporter in the brain or homozygous knockout of the transporter in the basal forebrain were compared with wild-type mice. Hippocampal and frontal cortical electrographic activity and righting reflex were studied in response to isoflurane and ketamine doses.
RESULTS
The loss-of-righting-reflex dose for isoflurane was lower in knockout (mean ± SD, 0.76 ± 0.08%, n = 18, P = 0.005) but not knockdown (0.78 ± 0.07%, n = 24, P = 0.021), as compared to wild-type mice (0.83 ± 0.07%, n = 23), using a significance criterion of P = 0.017 for three planned comparisons. Loss-of-righting-reflex dose for ketamine was lower in knockout (144 ± 39 mg/kg, n = 14, P = 0.006) but not knockdown (162 ± 32 mg/kg, n = 20, P = 0.602) as compared to wild-type mice (168 ± 24 mg/kg, n = 21). Hippocampal high-gamma (63 to 100 Hz) power after isoflurane was significantly lower in knockout and knockdown mice compared to wild-type mice (isoflurane-dose and mouse-group interaction effect, F[8,56] = 2.87, P = 0.010; n = 5 to 6 mice per group). Hippocampal high-gamma power after ketamine was significantly lower in both knockout and knockdown mice when compared to wild-type mice (interaction effect F[2,13] = 6.06, P = 0.014). The change in frontal cortical gamma power with isoflurane or ketamine was not statistically different among knockout, knockdown, and wild-type mice.
CONCLUSIONS
These findings suggest that forebrain cholinergic neurons modulate behavioral sensitivity and hippocampal gamma activity during isoflurane and ketamine anesthesia.
Topics: Acetylcholine; Anesthetics, Inhalation; Animals; Isoflurane; Ketamine; Male; Mice; Mice, Knockout; Models, Animal; Prosencephalon
PubMed: 33635947
DOI: 10.1097/ALN.0000000000003713 -
Current Biology : CB Jun 2023Switching behaviors from aggression to submission in losers at the end of conspecific social fighting is essential to avoid serious injury or death. We have previously...
Switching behaviors from aggression to submission in losers at the end of conspecific social fighting is essential to avoid serious injury or death. We have previously shown that the experience of defeat induces a loser-specific potentiation in the habenula (Hb)-interpeduncular nucleus (IPN) and show here that this is induced by acetylcholine. Calcium imaging and electrophysiological recording using acute brain slices from winners and losers of fighting behavior in zebrafish revealed that the ventral IPN (vIPN) dominates over the dorsal IPN in the neural response to Hb stimulation in losers. We also show that GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits on the postsynaptic membrane increased in the vIPN of losers. Furthermore, these loser-specific neural properties disappeared in the presence of an α7 nicotinic acetylcholine receptor (nAChR) antagonist and, conversely, were induced in brain slices of winners treated with α7 nAChR agonists. These data suggest that acetylcholine released from Hb terminals in the vIPN induces activation of α7 nAChR followed by an increase in postsynaptic membrane GluA1. This results in an increase in active synapses on postsynaptic neurons, resulting in the potentiation of neurotransmissions to the vIPN. This acetylcholine-induced neuromodulation could be the neural foundation for behavioral switching in losers. Our results could increase our understanding of the mechanisms of various mood disorders such as social anxiety disorder and social withdrawal.
Topics: Animals; Interpeduncular Nucleus; Receptors, Nicotinic; Glutamic Acid; Acetylcholine; Habenula; Zebrafish
PubMed: 37105168
DOI: 10.1016/j.cub.2023.03.087 -
FEBS Letters Jul 2020Acetylcholine (ACh) signaling orchestrates mammalian movement, mental capacities, and inflammation. Dysregulated ACh signaling associates with many human mental... (Review)
Review
Acetylcholine (ACh) signaling orchestrates mammalian movement, mental capacities, and inflammation. Dysregulated ACh signaling associates with many human mental disorders and neurodegeneration in an individual-, sex-, and tissue-related manner. Moreover, aged patients under anticholinergic therapy show increased risk of dementia, but the underlying molecular mechanisms are incompletely understood. Here, we report that certain cholinergic-targeting noncoding RNAs, named Cholino-noncoding RNAs (ncRNAs), can modulate ACh signaling, agonistically or antagonistically, via distinct direct and indirect mechanisms and at different timescales. Cholino-ncRNAs include both small microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). The former may attenuate translation and/or induce destruction of target mRNAs that code for either ACh-signaling proteins or transcription factors controlling the expression of cholinergic genes. lncRNAs may block miRNAs via 'sponging' events or by competitive binding to the cholinergic target mRNAs. Also, single nucleotide polymorphisms in either Cholino-ncRNAs or in their recognition sites in the ACh-signaling associated genes may modify ACh signaling-regulated processes. Taken together, both inherited and acquired changes in the function of Cholino-ncRNAs impact ACh-related deficiencies, opening new venues for individual, sex-related, and age-specific oriented research, diagnosis, and therapeutics.
Topics: Acetylcholine; Aging; Animals; Female; Humans; Male; RNA, Untranslated; Signal Transduction; Spatio-Temporal Analysis
PubMed: 32330292
DOI: 10.1002/1873-3468.13789