scholarly journals Light-Mediated Inhibition of Colonic Smooth Muscle Constriction and Colonic Motility via Opsin 3

2021 ◽  
Vol 12 ◽  
Author(s):  
William Dan ◽  
Ga Hyun Park ◽  
Shruti Vemaraju ◽  
Amy D. Wu ◽  
Kristina Perez ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Ex Vivo ◽  
Colonic Motility ◽  
Muscularis Propria ◽  
Receptor Activation ◽  
Enteric Neurons ◽  
Gastrointestinal Dysmotility ◽  
Protein Receptor ◽  
The Central Nervous System ◽  
Murine Colon

Opsin photoreceptors outside of the central nervous system have been shown to mediate smooth muscle photorelaxation in several organs. We hypothesized that opsin receptor activation in the colon would have a similar effect and influence colonic motility. We detected Opsin 3 (OPN3) protein expression in the colonic wall and demonstrated that OPN3 was present in enteric neurons in the muscularis propria of the murine colon. Precontracted murine colon segments demonstrated blue light (BL) -mediated relaxation ex vivo. This photorelaxation was wavelength specific and was increased with the administration of the chromophore 9-cis retinal and a G protein receptor kinase 2 (GRK2) inhibitor. Light-mediated relaxation of the colon was not inhibited by L-NAME or tetrodotoxin (TTX). Furthermore, BL exposure in the presence of 9-cis retinal decreased the frequency of colonic migrating motor complexes (CMMC) in spontaneously contracting mouse colons ex vivo. These results demonstrate for the first time a receptor-mediated photorelaxation of colonic smooth muscle and implicate opsins as possible new targets in the treatment of spasmodic gastrointestinal dysmotility.

scholarly journals Airway smooth muscle photorelaxation via opsin receptor activation

2019 ◽  
Vol 316 (1) ◽  
pp. L82-L93 ◽  
Author(s):  
Peter D. Yim ◽  
George Gallos ◽  
Jose F. Perez-Zoghbi ◽  
Yi Zhang ◽  
Dingbang Xu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Blue Light ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Receptor Activation ◽  
Upper Airways ◽  
Peripheral Airways ◽  
Protein Receptor ◽  
Calcium Activated Potassium Channels ◽  
Precision Cut Lung Slices

Nonvisual opsin (OPN) receptors have recently been implicated in blue light-mediated photorelaxation of smooth muscle in various organs. Since photorelaxation has not yet been demonstrated in airway smooth muscle (ASM) or in human tissues, we questioned whether functional OPN receptors are expressed in mouse and human ASM. mRNA, encoding the OPN 3 receptor, was detected in both human and mouse ASM. To demonstrate the functionality of the OPN receptors, we performed wire myography of ex vivo ASM from mouse and human upper airways. Blue light-mediated relaxation of ACh-preconstricted airways was intensity and wavelength dependent (maximum relaxation at 430-nm blue light) and was inhibited by blockade of the large-conductance calcium-activated potassium channels with iberiotoxin. We further implicated OPN receptors as key mediators in functional photorelaxation by demonstrating increased relaxation in the presence of a G protein receptor kinase 2 inhibitor or an OPN chromophore (9- cis retinal). We corroborated these responses in peripheral airways of murine precision-cut lung slices. This is the first demonstration of photorelaxation in ASM via an OPN receptor-mediated pathway.

scholarly journals Activity within specific enteric neurochemical subtypes is correlated with distinct patterns of gastrointestinal motility in the murine colon

2019 ◽  
Vol 317 (2) ◽  
pp. G210-G221 ◽  
Author(s):  
Thomas W. Gould ◽  
William A. Swope ◽  
Dante J. Heredia ◽  
Robert D. Corrigan ◽  
Terence K. Smith
Keyword(s):  
Smooth Muscle ◽  
Gastrointestinal Motility ◽  
Colonic Motility ◽  
Cholinergic Neurons ◽  
Muscle Contractions ◽  
Tonic Inhibition ◽  
Enteric Neurons ◽  
Synthesis Inhibitor ◽  
Smooth Muscle Contractions ◽  
Murine Colon

The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes (CMMCs) and 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns are unclear. Using transgenic animals expressing the genetically encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively. Nitrergic neurons [neuronal nitric oxide synthase (nNOS)-positive neurons] expressing GCaMP3 exhibited higher levels of activity during periods of tonic inhibition than during CMMCs. Consistent with these findings, optogenetic activation of ChR2 in nitrergic neurons depressed ongoing CMMCs. Conversely, cholinergic neurons [choline acetyltransferase (ChAT)-positive neurons] expressing GCaMP3 markedly increased their activity during the CMMC. Treatment with the NO synthesis inhibitor Nω-nitro-l-arginine also augmented the activity of ChAT-GCaMP3 neurons, suggesting that the reciprocal patterns of activity exhibited by nitrergic and cholinergic enteric neurons during distinct phases of colonic motility may be related. NEW & NOTEWORTHY Correlating the activity of neuronal populations in the myenteric plexus to distinct periods of gastrointestinal motility is complicated by the difficulty of measuring the activity of specific neuronal subtypes. Here, using mice expressing genetically encoded calcium indicators or the optical actuator channelrhodopsin-2, we provide compelling evidence that cholinergic and nitrergic neurons play important roles in mediating coordinated propagating peristaltic contractions or tonic inhibition, respectively, in the murine colon.

scholarly journals NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 147
Author(s):  
Romuald Brice Babou Kammoe ◽  
Gilles Kauffenstein ◽  
Julie Pelletier ◽  
Bernard Robaye ◽  
Jean Sévigny
Keyword(s):  
Smooth Muscle ◽  
Ex Vivo ◽  
Smooth Muscle Contraction ◽  
Receptor Activation ◽  
Nucleoside Triphosphate ◽  
Nucleotide Receptors ◽  
Nerve Terminals ◽  
Wild Type ◽  
Nucleoside Triphosphate Diphosphohydrolase ◽  
Bladder Contraction

Nucleotides released by smooth muscle cells (SMCs) and by innervating nerve terminals activate specific P2 receptors and modulate bladder contraction. We hypothesized that cell surface enzymes regulate SMC contraction in mice bladder by controlling the concentration of nucleotides. We showed by immunohistochemistry, enzymatic histochemistry, and biochemical activities that nucleoside triphosphate diphosphohydrolase-1 (NTPDase1) and ecto-5′-nucleotidase were the major ectonucleotidases expressed by SMCs in the bladder. RT-qPCR revealed that, among the nucleotide receptors, there was higher expression of P2X1, P2Y1, and P2Y6 receptors. Ex vivo, nucleotides induced a more potent contraction of bladder strips isolated from NTPDase1 deficient (Entpd1−/−) mice compared to wild type controls. The strongest responses were obtained with uridine 5′-triphosphate (UTP) and uridine 5′-diphosphate (UDP), suggesting the involvement of P2Y6 receptors, which was confirmed with P2ry6−/− bladder strips. Interestingly, this response was reduced in female bladders. Our results also suggest the participation of P2X1, P2Y2 and/or P2Y4, and P2Y12 in these contractions. A reduced response to the thromboxane analogue U46619 was also observed in wild type, Entpd1−/−, and P2ry6−/− female bladders showing another difference due to sex. In summary, NTPDase1 modulates the activation of nucleotide receptors in mouse bladder SMCs, and contractions induced by P2Y6 receptor activation were weaker in female bladders.

scholarly journals Androgen regulation of bowel function in mice and humans

2020 ◽  
Author(s):  
Daniella Rastelli ◽  
Ariel Robinson ◽  
Lynley T. Matthews ◽  
Kristina Perez ◽  
William Dan ◽  
...  
Keyword(s):  
Sex Differences ◽  
Smooth Muscle ◽  
Colonic Motility ◽  
Bowel Function ◽  
Free Testosterone ◽  
Enteric Neurons ◽  
Adult Mice ◽  
Digestive Disorder ◽  
Irritable Bowel

SummaryMany digestive disorders have prominent sex differences in incidence, symptomatology, and treatment response that are not well understood. Irritable bowel syndrome (IBS), for example, affects approximately 10% of the population worldwide and tends to have different manifestations in males and females. Androgens are steroid hormones present at much higher levels in post-pubertal males than females and could be involved in these sex differences, but their normal functions in the bowel are largely unknown. Here, we show that gonadal androgens are required for normal gastrointestinal motility in vivo. In the healthy mouse gut, we detected androgen receptors in smooth muscle cells and a subset of enteric neurons. Surgical or genetic disruption of androgen signaling in adult mice selectively and reversibly altered colonic motility by affecting neurons rather than smooth muscle. To determine if androgens also influence human bowel function, we measured androgen levels in 208 adults with IBS. Free testosterone levels were lower in patients with IBS compared to healthy controls and inversely correlated with symptom severity. Taken together, these observations establish a role for androgens in the regulation of colonic motility and link altered androgen signaling with a common digestive disorder. These findings advance the fundamental understanding of gut motility, with implications for normal aging and disorders involving the gut-brain axis.

Mast Cell Effects on Esophageal Smooth Muscle and their Potential Role in Eosinophilic Esophagitis and Achalasia

2020 ◽  
Author(s):  
Melissa R Nelson ◽  
Xi Zhang ◽  
Zui Pan ◽  
Stuart Jon Spechler ◽  
Rhonda F. Souza
Keyword(s):  
Mast Cell ◽  
Smooth Muscle ◽  
Mast Cells ◽  
Muscle Contraction ◽  
Eosinophilic Esophagitis ◽  
Muscularis Propria ◽  
Smooth Muscle Contraction ◽  
Enteric Neurons ◽  
Mast Cell Activation ◽  
Parkinson’S Diseases

Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscularis propria might cause esophageal motility abnormalities, including the failure of lower esophageal sphincter relaxation typical of achalasia. In addition, mast cells have been implicated in the pathogenesis of a number of neurodegenerative disorders of the central nervous system such as Alzheimer's and Parkinson's diseases, because degranulating mast cells release pro-inflammatory and cytotoxic mediators capable of damaging neurons. Such mast cell degranulation in the myenteric plexus of the esophagus could cause the loss of enteric neurons that characterizes achalasia. In this report, we review the molecular mechanisms of esophageal smooth muscle contraction, and how mast cells products might affect that muscle and cause neurodegeneration in the esophagus. Based on these data, we present our novel, conceptual model for an allergy-induced form of achalasia mediated by mast cell activation in the esophageal muscularis propria.

scholarly journals An Indole Alkaloid Extracted from Evodia rutaecarpa Inhibits Colonic Motility of Rats In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Guo-xiang Wang ◽  
Yan-li Xiang ◽  
Hong-gang Wang ◽  
Yang-de Miu ◽  
Guang Yu
Keyword(s):  
Smooth Muscle ◽  
Calcium Channels ◽  
Smooth Muscle Cells ◽  
Gastrointestinal Motility ◽  
Colonic Motility ◽  
Indole Alkaloid ◽  
Enteric Neurons ◽  
Relaxant Effect ◽  
Evodia Rutaecarpa

Evodiamine (Evo) is an indole alkaloid extracted from the traditional Chinese medicinal herb Evodia rutaecarpa. Evo may regulate gastrointestinal motility, but the evidence is insufficient, and the mechanisms remain unknown. The aim of this study was to investigate the effect of Evo on colonic motility of rats and the underlying mechanisms in vitro. Rat colonic muscle was exposed to Evo (10 and 100 μM) followed by immunohistochemistry of cholecystokinin receptor 1 (CCK1R). Muscle contractions were studied in an organ bath system to determine whether CCK1R, nitric oxide (NO), and enteric neurons are involved in the relaxant effect of Evo. Whole-cell patch-clamp was used to detect L-type calcium currents (ICa,L) in isolated colonic smooth muscle cells (SMCs). CCK1R was observed in SMCs, intermuscular neurons, and mucosa of rat colon. Evo could inhibit spontaneous muscle contractions; NO synthase, inhibitor L-NAME CCK1R antagonist, could partly block this effect, while the enteric neurons may not play a major role. Evo inhibited the peak ICa,L in colonic SMCs at a membrane potential of 0 mV. The current-voltage (I–V) relationship of L-type calcium channels was modified by Evo, while the peak of the I–V curve remained at 0 mV. Furthermore, Evo inhibited the activation of L-type calcium channels and decreased the peak ICa,L. The relaxant effect of Evo on colonic muscle is associated with the inhibition of L-type calcium channels. The enteric neurons, NO, and CCK1R may be partly related to the inhibitory effect of Evo on colonic motility. This study provides the first evidence that evodiamine can regulate colonic motility in rats by mediating calcium homeostasis in smooth muscle cells. These data form a theoretical basis for the clinical application of evodiamine for treatment of gastrointestinal motility diseases.

Central Histamine, the H3-Receptor and Obesity Therapy

2019 ◽  
Vol 18 (7) ◽  
pp. 516-522
Author(s):  
Néstor F. Díaz ◽  
Héctor Flores-Herrera ◽  
Guadalupe García-López ◽  
Anayansi Molina-Hernández
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Animal Studies ◽  
Energy Homeostasis ◽  
Receptor Activation ◽  
Receptor Ligands ◽  
Histaminergic System ◽  
H3 Receptor ◽  
Weight One ◽  
The Central Nervous System

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

scholarly journals Bladder Cancer Involving Smooth Muscle of Indeterminate Type or Muscularis Mucosae in Transurethral Biopsy Specimens

2020 ◽  
Vol 154 (2) ◽  
pp. 208-214
Author(s):  
Michael J Hwang ◽  
Ashish M Kamat ◽  
Colin P Dinney ◽  
Bogdan Czerniak ◽  
Charles C Guo
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Smooth Muscle ◽  
Clinical Outcome ◽  
Survival Time ◽  
Transurethral Resection ◽  
Muscularis Propria ◽  
Clinicopathologic Features ◽  
Muscularis Mucosae ◽  
Biopsy Specimens

Abstract Objectives Bladder cancers invading the muscularis mucosae (MM) are treated differently from those invading the muscularis propria (MP). However, it may be difficult to determine the type of smooth muscle in transurethral resection (TUR) or biopsy specimens. We aimed to investigate the clinicopathologic features of bladder cancers involving smooth muscle of indeterminate type (SMIT) in TUR specimens in comparison with those invading the MM. Methods We identified 103 patients with bladder cancer involving SMIT (n = 27) or the MM (n = 76) in TUR specimens. All patients underwent subsequent restaging TUR or cystectomy. Results Bladder cancer with SMIT invasion showed a significantly higher rate of MP invasion in the subsequent specimens than those invading the MM (52% vs 29%). Lack of MP in the TUR specimens had a significantly higher risk of MP invasion in the subsequent specimens than those with the MP (61% vs 40%). The overall survival time for patients with SMIT invasion was significantly shorter than those with MM invasion. Conclusions Bladder cancers with SMIT invasion in TUR specimens show more frequent cancer upstaging in the subsequent specimens and a poorer clinical outcome than those invading the MM, which highlights the importance of a cancer restaging procedure for these patients.

Autoimmune encephalitis and gastrointestinal dysmotility: achalasia, gastroparesis, and slow transit constipation

2020 ◽  
Vol 58 (10) ◽  
pp. 975-981
Author(s):  
Thomas Frieling ◽  
Christian Kreysel ◽  
Michael Blank ◽  
Dorothee Müller ◽  
Ilka Melchior ◽  
...  
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Autoimmune Encephalitis ◽  
Enteric Neurons ◽  
Slow Transit Constipation ◽  
Gastrointestinal Dysmotility ◽  
Slow Transit ◽  
Small Intestinal ◽  
Interdigestive Motility ◽  
Cells Of Cajal ◽  
Transit Constipation

Abstract Background Neurological autoimmune disorders (NAD) are caused by autoimmune inflammation triggered by specific antibody subtypes. NAD may disturb the gut-brain axis at several levels including brain, spinal cord, peripheral, or enteric nervous system. Case report We present a case with antinuclear neuronal Hu (ANNA-1)- and antiglial nuclear (SOX-1) autoimmune antibody-positive limbic encephalitis and significant gastrointestinal dysmotility consisting of achalasia type II, gastroparesis, altered small intestinal interdigestive motility, and severe slow transit constipation. The autoantibodies of the patient’s serum labeled enteric neurons and interstitial cells of Cajal but no other cells in the gut wall. Achalasia was treated successfully by pneumatic cardia dilation and gastrointestinal dysmotility successfully with prucalopride. Conclusion NAD may disturb gastrointestinal motility by altering various levels of the gut-brain axis.

scholarly journals Combination of histochemical analyses and micro-MRI reveals regional changes of the murine cervix in preparation for labor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antara Chatterjee ◽  
Rojan Saghian ◽  
Anna Dorogin ◽  
Lindsay S. Cahill ◽  
John G. Sled ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Muscle Cells ◽  
Pregnant Mouse ◽  
Collagen Fibers ◽  
Muscular Layer ◽  
Tissue Organization ◽  
Picrosirius Red

AbstractThe cervix is responsible for maintaining pregnancy, and its timely remodeling is essential for the proper delivery of a baby. Cervical insufficiency, or “weakness”, may lead to preterm birth, which causes infant morbidities and mortalities worldwide. We used a mouse model of pregnancy and term labor, to examine the cervical structure by histology (Masson Trichome and Picrosirius Red staining), immunohistochemistry (Hyaluronic Acid Binding Protein/HABP), and ex-vivo MRI (T2-weighted and diffusion tensor imaging), focusing on two regions of the cervix (i.e., endocervix and ectocervix). Our results show that mouse endocervix has a higher proportion of smooth muscle cells and collagen fibers per area, with more compact tissue structure, than the ectocervix. With advanced gestation, endocervical changes, indicative of impending delivery, are manifested in fewer smooth muscle cells, expansion of the extracellular space, and lower presence of collagen fibers. MRI detected three distinctive zones in pregnant mouse endocervix: (1) inner collagenous layer, (2) middle circular muscular layer, and (3) outer longitudinal muscular layer. Diffusion MRI images detected changes in tissue organization as gestation progressed suggesting the potential application of this technique to non-invasively monitor cervical changes that precede the onset of labor in women at risk for preterm delivery.

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