Diversity of neurogenic smooth muscle electrical rhythmicity in mouse proximal colon

2020 ◽  
Vol 318 (2) ◽  
pp. G244-G253 ◽  
Author(s):  
Nick J. Spencer ◽  
Lee Travis ◽  
Lukasz Wiklendt ◽  
Timothy J. Hibberd ◽  
Marcello Costa ◽  
...  

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1–2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle. NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nick J. Spencer ◽  
Lee Travis ◽  
Lukasz Wiklendt ◽  
Marcello Costa ◽  
Timothy J. Hibberd ◽  
...  

AbstractHow the Enteric Nervous System (ENS) coordinates propulsion of content along the gastrointestinal (GI)-tract has been a major unresolved issue. We reveal a mechanism that explains how ENS activity underlies propulsion of content along the colon. We used a recently developed high-resolution video imaging approach with concurrent electrophysiological recordings from smooth muscle, during fluid propulsion. Recordings showed pulsatile firing of excitatory and inhibitory neuromuscular inputs not only in proximal colon, but also distal colon, long before the propagating contraction invades the distal region. During propulsion, wavelet analysis revealed increased coherence at ~2 Hz over large distances between the proximal and distal regions. Therefore, during propulsion, synchronous firing of descending inhibitory nerve pathways over long ranges aborally acts to suppress smooth muscle from contracting, counteracting the excitatory nerve pathways over this same region of colon. This delays muscle contraction downstream, ahead of the advancing contraction. The mechanism identified is more complex than expected and vastly different from fluid propulsion along other hollow smooth muscle organs; like lymphatic vessels, portal vein, or ureters, that evolved without intrinsic neurons.


2010 ◽  
Vol 19 (18) ◽  
pp. 3642-3651 ◽  
Author(s):  
Maria M. Alves ◽  
Grzegorz Burzynski ◽  
Jean-Marie Delalande ◽  
Jan Osinga ◽  
Annemieke van der Goot ◽  
...  

Abstract Goldberg–Shprintzen syndrome (GOSHS) is a rare clinical disorder characterized by central and enteric nervous system defects. This syndrome is caused by inactivating mutations in the Kinesin Binding Protein (KBP) gene, which encodes a protein of which the precise function is largely unclear. We show that KBP expression is up-regulated during neuronal development in mouse cortical neurons. Moreover, KBP-depleted PC12 cells were defective in nerve growth factor-induced differentiation and neurite outgrowth, suggesting that KBP is required for cell differentiation and neurite development. To identify KBP interacting proteins, we performed a yeast two-hybrid screen and found that KBP binds almost exclusively to microtubule associated or related proteins, specifically SCG10 and several kinesins. We confirmed these results by validating KBP interaction with one of these proteins: SCG10, a microtubule destabilizing protein. Zebrafish studies further demonstrated an epistatic interaction between KBP and SCG10 in vivo . To investigate the possibility of direct interaction between KBP and microtubules, we undertook co-localization and in vitro binding assays, but found no evidence of direct binding. Thus, our data indicate that KBP is involved in neuronal differentiation and that the central and enteric nervous system defects seen in GOSHS are likely caused by microtubule-related defects.


2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Conor J. McCann ◽  
Julie E. Cooper ◽  
Dipa Natarajan ◽  
Benjamin Jevans ◽  
Laura E. Burnett ◽  
...  

2018 ◽  
Vol 38 (24) ◽  
pp. 5507-5522 ◽  
Author(s):  
Nick J. Spencer ◽  
Timothy J. Hibberd ◽  
Lee Travis ◽  
Lukasz Wiklendt ◽  
Marcello Costa ◽  
...  

2014 ◽  
Vol 34 (31) ◽  
pp. 10361-10378 ◽  
Author(s):  
M. Seifi ◽  
J. F. Brown ◽  
J. Mills ◽  
P. Bhandari ◽  
D. Belelli ◽  
...  

2017 ◽  
Author(s):  
Qianqian Wang ◽  
Ke Wang ◽  
R. Sergio Solorzano-Vargas ◽  
Po-Yu Lin ◽  
Christopher M. Walthers ◽  
...  

AbstractAlthough critical for studies of gut motility and intestinal regeneration, the in vitro culture of intestinal muscularis with peristaltic function remains a significant challenge. Periodic contractions of intestinal muscularis result from the coordinated activity of smooth muscle cells (SMC), the enteric nervous system (ENS), and interstitial cells of Cajal (ICC). Reproducing this activity requires the preservation of all these cells in one system. Here we report the first serum-free culture methodology that consistently maintains spontaneous and periodic contractions of murine and human intestinal muscularis cells for months. In this system, SMC expressed the mature marker myosin heavy chain, and multipolar/dipolar ICC, uniaxonal/multipolar neurons and glial cells were present. Furthermore, drugs affecting ENS, ICC or SMC altered the contractions. Combining this method with scaffolds, contracting cell sheets were formed with organized architecture. With the addition of intestinal epithelial cells, this platform enabled at least 9 types of cells from mucosa and muscularis to coexist and function. The method constitutes a powerful tool for mechanistic studies of gut motility disorders and the regeneration of full-thickness engineered intestine.In the small intestine, the mucosa processes partially digested food and absorbs nutrients while the muscularis actuates the peristaltic flow to transport luminal content aborally. Gut motility is central to its digestive and absorptive function. The intestinal muscularis contains various types of cells: of these, smooth muscle cells, the enteric nervous system (ENS)1,2, and the pacemaker interstitial cells of Cajal (ICC)3 are three important players involved in the development of gut motility. Recent studies on intestinal tissue engineering have highlighted the importance of regenerating the functional intestinal muscularis4–9. A variety of systems derived from different cell sources, including pluripotent stem cells (PSC)4–6, embryonic stem cells (ESC)7 and primary tissue8,9, have been established to accomplish this goal and different contractile activities were developed in these systems. Notably, spontaneous contractions have been generated in culture systems that contained both ICC and smooth muscle cells4,6,10–13. In addition, electrical-induced neurogenic contractions were also successfully produced4,5,8 when ENS was introduced into culture. In one of the most recent studies, both spontaneous contractions and electrical-induced neurogenic contractions were developed in a PSC-based culture system4.


2019 ◽  
Vol 317 (3) ◽  
pp. G304-G313 ◽  
Author(s):  
Ivan M. Lang ◽  
Bidyut K. Medda ◽  
Reza Shaker

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats ( n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5–11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1–7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1–7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux.NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.


Author(s):  
Jesse J DiCello ◽  
Simona Elisa Carbone ◽  
Ayame Saito ◽  
Vi Pham ◽  
Agata Szymaszkiewicz ◽  
...  

Background and Purpose: Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models. Experimental Approach: The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo. Key Results: BMS-986187 displayed DOR selective PAM-agonist activity and orthosteric agonist probe-dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively. Conclusion and Implications: DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for treatment of gastrointestinal motility disorders.


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