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Jixiang Zhang, Shao-Rui Chen, Hong Chen, Hui-Lin Pan
Neuropathic pain is associated with persistent changes in gene expression in primary sensory neurons, but the underlying epigenetic mechanisms that cause these changes remain unclear. The muscarinic cholinergic receptors (mAChRs), particularly the M2 subtype (encoded by the cholinergic receptor muscarinic 2 [Chrm2] gene), are critically involved in the regulation of spinal nociceptive transmission. However, little is known about how Chrm2 expression is transcriptionally regulated. Here we show that nerve injury persistently increased the expression of RE1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor [NRSF]), a gene-silencing transcription factor, in the dorsal root ganglion (DRG)...
October 16, 2018: Journal of Biological Chemistry
Aaron M Bender, Aaron T Garrison, Craig W Lindsley
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned, and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor's role in physiological processes related to Alzheimer's disease, schizophrenia and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology...
October 3, 2018: ACS Chemical Neuroscience
Yuka Saito, Masato Mashimo, Akari Nobeyama, Kana Murakami, Takeshi Fujii
Lymphocytic cholinergic system has important roles in T cell functions, including immune responses and proliferation and differentiation of immune cells. T lymphocytes exclusively produces acetylcholine (ACh) via choline acetyltransferase (ChAT), activating their muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) in an autocrine and paracrine manners. Hippocampal cholinergic neurostimulating peptide (HCNP) is an undecapeptide cleaved from N-terminal of phosphatidylethanolamine-binding protein 1 (PEBP1)...
2018: Biological & Pharmaceutical Bulletin
Ee Von Moo, Patrick M Sexton, Arthur Christopoulos, Celine Valant
Muscarinic acetylcholine receptors (mAChRs) are exemplar models for understanding G protein-coupled receptor (GPCR) allostery, possessing a "common" allosteric site in an extracellular vestibule (ECV) for synthetic modulators including gallamine, strychnine, and brucine. In addition, there is intriguing evidence of endogenous peptides/proteins that may target this region at the M2 mAChR. A common feature of synthetic and endogenous M2 mAChR negative allosteric modulators (NAMs) is their cationic nature...
November 2018: Molecular Pharmacology
Norman Chinweike Asogwa, Chihiro Mori, Miguel Sánchez-Valpuesta, Shin Hayase, Kazuhiro Wada
Acetylcholine receptors (AChRs) abound in the central nervous system of vertebrates. Muscarinic AChRs (mAChRs), a functional subclass of AChRs, mediate neuronal responses via intracellular signal transduction. They also play roles in sensorimotor co-ordination and motor skill learning by enhancing cortical plasticity. Learned birdsong is a complex motor skill acquired through sensorimotor coordination during a critical period. However, the functions of AChRs in the neural circuits for vocal learning and production remain largely unexplored...
September 10, 2018: Journal of Comparative Neurology
Shu Wang, Yanan Jiang, Jingling Chen, Changliang Dai, Dandan Liu, Wei Pan, Lijuan Wang, Moyondafoluwa Blessing Fasae, Lihua Sun, Lanfeng Wang, Yan Liu
BACKGROUND/AIMS: Because the prevalence of age-related cardiac impairment increases as the human lifespan increases, it is important to combat the effects of aging. Recently, the cardiac M3 muscarinic acetylcholine receptor (M3-mAChR) has been demonstrated to play important roles in cardiac development and in the pathogenesis of cardiac diseases. However, the role of M3-mAChR in aging remains largely unknown. Therefore, the aim of this study was to investigate the involvement of M3-mAChR in the progression of cardiac aging...
2018: Cellular Physiology and Biochemistry
Estella Zuccolo, Umberto Laforenza, Sharon Negri, Laura Botta, Roberto Berra-Romani, Pawan Faris, Giorgia Scarpellino, Greta Forcaia, Giorgia Pellavio, Giulio Sancini, Francesco Moccia
Basal forebrain neurons control cerebral blood flow (CBF) by releasing acetylcholine (Ach), which binds to endothelial muscarinic receptors to induce nitric (NO) release and vasodilation in intraparenchymal arterioles. Nevertheless, the mechanism whereby Ach stimulates human brain microvascular endothelial cells to produce NO is still unknown. Herein, we sought to assess whether Ach stimulates NO production in a Ca2+ -dependent manner in hCMEC/D3 cells, a widespread model of human brain microvascular endothelial cells...
September 7, 2018: Journal of Cellular Physiology
Wessel A C Burger, Patrick M Sexton, Arthur Christopoulos, David M Thal
Recent breakthroughs and developments in structural biology have led to a spate of crystal structures for G protein-coupled receptors (GPCRs). This is the case for the muscarinic acetylcholine receptors (mAChRs) where inactive-state structures for four of the five subtypes and two active-state structures for one subtype are available. These mAChR crystal structures have provided new insights into receptor mechanisms, dynamics, and allosteric modulation. This is highly relevant to the mAChRs given that these receptors are an exemplar model system for the study of GPCR allostery...
October 1, 2018: Journal of General Physiology
Teresa Mann, Karl Zilles, Felix Klawitter, Markus Cremer, Alexander Hawlitschka, Nicola Palomero-Gallagher, Oliver Schmitt, Andreas Wree
Cholinergic neurotransmission has a pivotal function in the caudate-putamen, and is highly associated with the pathophysiology of Parkinson's disease. Here, we investigated long-term changes in the densities of the muscarinic receptor subtypes M1 , M2 , M3 (mAchRs) and the nicotinic receptor subtype α4 β2 (nAchRs) in the striatum of the 6-OHDA-induced hemiparkinsonian (hemi-PD) rat model using quantitative in vitro receptor autoradiography. Hemi-PD rats exhibited an ipsilateral decrease in striatal mAchR densities between 6 and 16%...
2018: Frontiers in Neuroanatomy
Mari Endo, Masatoshi Hori, Hiroshi Ozaki, Tetsuro Oikawa, Hiroshi Odaguchi, Toshihiko Hanawa
Zingiberis processum rhizoma (ZPR) is a major active component of daikenchuto (DKT), which induces anti-inflammatory action by inhibiting macrophage infiltration. However, it is unclear whether ZPR is related to DKT-induced anti-inflammatory action via a reduction of neutrophil infiltration against postoperative ileus (POI). In this study, we orally administered individual herbal components of DKT to mice four times before and after intestinal manipulation (IM). The anti-inflammatory action of each crude drug was evaluated by histochemical analysis of relevant molecules...
August 2018: Journal of Pharmacological Sciences
Kannaporn Intachai, Siriporn C Chattipakorn, Nipon Chattipakorn, Krekwit Shinlapawittayatorn
Acute myocardial infarction (AMI) is the most common cause of acute myocardial injury and its most clinically significant form. The most effective treatment for AMI is to restore an adequate coronary blood flow to the ischemic myocardium as quickly as possible. However, reperfusion of an ischemic region can induce cardiomyocyte death, a phenomenon termed "myocardial ischemia/reperfusion (I/R) injury". Disruption of cardiac parasympathetic (vagal) activity is a common hallmark of a variety of cardiovascular diseases including AMI...
August 21, 2018: International Journal of Molecular Sciences
Yulia V Dobryakova, Olga Y Ivanova, Vladimir A Markevich
Muscarinic acetylcholine receptors (mAChR) are known to be related to learning and memory processes. Inactivation of mAChR by cholinergic antagonists have been shown to produce amnesia in a variety of behavioral tasks. In this study, we investigated the role of M1 and M2 AChR on passive avoidance learning and plasticity of synapses formed by Schaffer collaterals in freely moving rats. Experiments were performed using Wistar male rats. Seven days before testing, a recording electrode was lowered in the CA1 region under chloral hydrate anaesthesia to record the field excitatory postsynaptic potential (fEPSP) in response to Schaffer collateral stimulation...
2018: Acta Neurobiologiae Experimentalis
Yong Beom Kim, Hong-Seuk Yang, Ha Jung Kim, Hey-Ran Choi, Junyong In, Soon-Young Yoon, Young Jin Ro
This in vivo study tested the hypothesis that the modulation of acetylcholine (ACh) release by the M1 muscarinic receptor (mAChR) in the neuromuscular junction of disused muscles may affect the tensions of the muscles during the neuromuscular monitoring of a rocuronium-induced neuromuscular block and compared the results with those obtained from normal muscles. A total of 20 C57BL/6 (wild-type) and 10 α7 knock out (α7KO) mice were used in this experiment. As a pre-experimental procedure, knee and ankle joints of right hind limbs were fixed by needle pinning at the 90° flexed position...
July 13, 2018: Clinical and Experimental Pharmacology & Physiology
Mélissa Sourioux, Sandrine S Bertrand, Jean-René Cazalets
Here, we investigated intrinsic spinal cord mechanisms underlying the physiological requirement for autonomic and somatic motor system coupling. Using an in vitro spinal cord preparation from newborn rat, we demonstrate that the specific activation of muscarinic cholinergic receptors (mAchRs) (with oxotremorine) triggers a slow burst rhythm in thoracic spinal segments, thereby revealing a rhythmogenic capability in this cord region. Whereas axial motoneurons (MNs) were rhythmically activated during both locomotor activity and oxotremorine-induced bursting, intermediolateral sympathetic preganglionic neurons (IML SPNs) exhibited rhythmicity solely in the presence of oxotremorine...
July 2018: PLoS Biology
Rui Tan, You Mee Ahn, Hye Yoom Kim, Yun Jung Lee, Kyung Woo Cho, Dae Gill Kang, Ho Sub Lee
In the present study, the change in secretion of atrial natriuretic peptide (ANP) from the atria was defined in hypertension accompanied by ventricular hypertrophy and increased synthesis of ANP. To identify the change of the secretion and mechanisms involved, experiments were performed in isolated perfused beating atria from sham-operated normotensive and renovascular hypertensive rats. Expression of ANP, natriuretic peptide receptor (NPR)-C, components of the renin-angiotensin system, and muscarinic signaling pathway was measured in cardiac tissues...
September 1, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Ji Eun Kim, Mi Rim Lee, Jin Ju Park, Jun Young Choi, Bo Ram Song, Hong Joo Son, Young Whan Choi, Kyung Mi Kim, Jin Tae Hong, Dae Youn Hwang
CONTEXT: Quercetin (QCT) has been known as a potential therapeutic strategy for gastrointestinal diseases because it contributes to the stabilization of mast cells, the prevention of histamine release and modulation of CaCC chloride channel. OBJECTIVE: We investigated the laxative effect and action mechanism of QCT in Lop-induced constipation model. MATERIALS AND METHODS: Constipation of SD rats was induced by subcutaneous injection of loperamide (Lop) (4 mg/kg weight) in 0...
December 2018: Pharmaceutical Biology
Toshiaki Ishizuka, Ayako Ozawa, Mieko Katsuura, Sayaka Nomura, Yasushi Satoh
Muscarinic acetylcholine receptors (mAchRs), which are expressed in various embryonic cells, may regulate neuronal differentiation. In the present study, we examined the effects of mAchR stimulation on the differentiation of mouse induced pluripotent stem (iPS) cells into neural progenitor cells (NPCs). Mouse iPS cells were cultured on ultra-low attachment dishes to induce embryoid body (EB) formation. All-trans retinoic acid (ATRA, 3 μmol/L) and/or pilocarpine (10 or 100 μmol/L), a mAchR agonist, were added to EB cultures for 4 days, following which the EBs were cultured on gelatin-coated plates for 7 days...
June 19, 2018: Clinical and Experimental Pharmacology & Physiology
Samuel T Kissinger, Alexandr Pak, Yu Tang, Sotiris C Masmanidis, Alexander A Chubykin
Familiarity of the environment changes the way we perceive and encode incoming information. However, the neural substrates underlying this phenomenon are poorly understood. Here we describe a new form of experience-dependent low-frequency oscillations in the primary visual cortex (V1) of awake adult male mice. The oscillations emerged in visually evoked potentials and single-unit activity following repeated visual stimulation. The oscillations were sensitive to the spatial frequency content of a visual stimulus and required the mAChRs for their induction and expression...
July 4, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Brittany J Carr, Koichiro Mihara, Rithwik Ramachandran, Mahmoud Saifeddine, Neil M Nathanson, William K Stell, Morley D Hollenberg
Purpose: Myopia is a refractive disorder that degrades vision. It can be treated with atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, but the mechanism is unknown. Atropine may block α-adrenoceptors at concentrations ≥0.1 mM, and another potent myopia-inhibiting ligand, mamba toxin-3 (MT3), binds equally well to human mAChR M4 and α1A- and α2A-adrenoceptors. We hypothesized that mAChR antagonists could inhibit myopia via α2A-adrenoceptors, rather than mAChR M4...
June 1, 2018: Investigative Ophthalmology & Visual Science
Chelsea T Tiernan, Stephen D Ginsberg, Bin He, Sarah M Ward, Angela L Guillozet-Bongaarts, Nicholas M Kanaan, Elliott J Mufson, Scott E Counts
Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling...
September 2018: Neurobiology of Disease
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