Interstitial cells of Cajal mediate nitrergic inhibitory neurotransmission in the murine gastrointestinal tract

Lies, Barbara; Gil, Víctor; Groneberg, Dieter; Seidler, Barbara; Saur, Dieter; Wischmeyer, Erhard; Jiménez, Marcel; Friebe, Andreas

doi:10.1152/ajpgi.00082.2014

Cited by 51 publications

(72 citation statements)

References 39 publications

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“…␤ 1 -trafficking, changes in post translational modification). NO is involved in rapid anterograde trafficking of ␤ 1 -subunit from the endosomes to the cell membrane and helps ␤ 1 -subunit to associate with BK ␣-subunit elevating channel Ca 2ϩ sensitivity in myocytes (36). Therefore, trafficking of the ␤ 1 -subunit to the cell membrane may be impaired in HFD mice.…”

Section: Discussionmentioning

confidence: 99%

“…BK ␤ 1 -subunit downregulation contributes to hypertension (67), heart failure (62), urinary bladder over activity (43) and impaired colonic motility (19). Although obesity (28), oxidative stress (52,56), and NO availability (36) all modulate the function or expression of ␤ 1 -subunits in vascular SMCs, it is unclear if similar modulation occurs in GI SMCs.…”

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confidence: 99%

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High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

Bhattarai

Fried

Gulbransen

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon. Am J Physiol Gastrointest Liver Physiol 311: G210 -G220, 2016. First published June 10, 2016; doi:10.1152/ajpgi.00085.2016.-We tested the hypothesis that colonic enteric neurotransmission and smooth muscle cell (SMC) function are altered in mice fed a high-fat diet (HFD). We used wild-type (WT) mice and mice lacking the ␤1-subunit of the BK channel (BK␤1 Ϫ/Ϫ ). WT mice fed a HFD had increased myenteric plexus oxidative stress, a 28% decrease in nitrergic neurons, and a 20% decrease in basal nitric oxide (NO) levels. Circular muscle inhibitory junction potentials (IJPs) were reduced in HFD WT mice. The NO synthase inhibitor nitro-L-arginine (NLA) was less effective at inhibiting relaxations in HFD compared with control diet (CD) WT mice (11 vs. 37%, P Ͻ 0.05). SMCs from HFD WT mice had depolarized membrane potentials (Ϫ47 Ϯ 2 mV) and continuous action potential firing compared with CD WT mice (Ϫ53 Ϯ 2 mV, P Ͻ 0.05), which showed rhythmic firing. SMCs from HFD or CD fed BK␤1 Ϫ/Ϫ mice fired action potentials continuously. NLA depolarized membrane potential and caused continuous firing only in SMCs from CD WT mice. Sodium nitroprusside (NO donor) hyperpolarized membrane potential and changed continuous to rhythmic action potential firing in SMCs from HFD WT and BK␤1 Ϫ/Ϫ mice. Migrating motor complexes were disrupted in colons from BK␤1 Ϫ/Ϫ mice and HFD WT mice. BK channel ␣-subunit protein and ␤1-subunit mRNA expression were similar in CD and HFD WT mice. We conclude that HFD-induced obesity disrupts inhibitory neuromuscular transmission, SMC excitability, and colonic motility by promoting oxidative stress, loss of nitrergic neurons, and SMC BK channel dysfunction. enteric nervous system; large conductance calcium-activated K ϩ channel; gastrointestinal motility; obesity A HIGH-FAT DIET (HFD) can cause obesity (35) that leads to an increased risk for the development of type 2 diabetes (13,17,33), heart disease (29, 33), and arthritis (25). Obesity is also associated with gastrointestinal (GI) dysmotility (15,35,41,63). GI motility is controlled largely by interactions between enteric neurons, interstitial cells of Cajal (ICCs), and smooth muscle cells (SMCs) but how obesity alters the function of these cells is poorly understood.A HFD is associated with increased oxidative stress and altered function of myenteric neurons in rodent models of obesity (11,60,61). The neuropathological changes that cause GI dysmotility vary among animal models and location in the GI tract (11). Inhibitory motor neurons that express nitric oxide synthase (NOS) are most susceptible to damage caused by obesity (3, 10, 11). These neurons are crucial for coordination of SMC relaxation (23, 41). Thus the disruption of nitrergic neuron function is a mechanism that contributes to HFDinduced GI dysmotility.Enteric motorneurons regulate propulsive motility patterns while GI SMCs have rhythmic electrical activ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

Bhattarai

Fried

Gulbransen

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In this study it was shown that NO-GC was expressed in several cell types including ICC and SMCs. To determine the role of NO-GC in each cell type, Lies et al 221 …”

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confidence: 99%

The Significance of Interstitial Cells in Neurogastroenterology

Blair¹,

Rhee²,

Sanders³

et al. 2014

J Neurogastroenterol Motil

116

111

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Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα + ) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα + cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.

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“…The development of conditional knockouts deficient in receptors/pathways for some cell subtypes opens up multiple research possibilities in this setting. An example is the above-mentioned study by Lies et al (73), carried out in a mouse deficient for sGC (the receptor mediating NO relaxation) only in ICCs or only in smooth muscle cells. Their findings showed that loss of this receptor in ICCs greatly reduced neurotransmission (hyperpolarization or IJPs), but a functional portion remained, which suggests that both hypotheses might be compatible (partly direct and partly indirect).…”

Section: Direct Vs Indirect Actionmentioning

confidence: 99%

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Gallego¹,

Mañé²,

Gil³

et al. 2016

Rev Esp Enferm Dig

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The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric motor neurons are classified into afferent neurons, interneurons and motorneurons. Motorneurons are excitatory or inhibitory causing smooth muscle contraction and relaxation respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or the descending phase of the peristaltic reflex. Nitric oxide (NO) and ATP or a related purine are the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP is an inhibitory neurotransmitter together with NO. The P2Y1 receptor has been identified as a the purine receptor responsible for smooth muscle relaxation. Although, probably, no clinician doubts about the significance of NO in the pathophysiology of gastrointestinal motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation.

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Interstitial cells of Cajal mediate nitrergic inhibitory neurotransmission in the murine gastrointestinal tract

Cited by 51 publications

References 39 publications

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

The Significance of Interstitial Cells in Neurogastroenterology

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

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