Communication via gap junctions modulates bile secretion in the isolated perfused rat liver

Nathanson, Michael H.; Rios-Velez, Laura; Burgstahler, Angela D.; Mennone, Albert

doi:10.1016/s0016-5085(99)70021-1

Cited by 70 publications

(64 citation statements)

References 26 publications

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“…GA in either the ␣-or ␤-isoform has been widely used to examine the functional role of gap junctions in smooth muscles using several assays, including electrical measurements, dye coupling, or intracellular Ca 2ϩ measurements. 18␣-GA was shown to abolish coupling through gap junctions using these assays in a variety of smooth muscle preparations (15,27,35,36,44).…”

Section: Discussionmentioning

confidence: 96%

Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells

Takeda¹,

Ward²,

Sanders³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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In the tunica muscularis of the gastrointestinal (GI) tract, gap junctions form low-resistance pathways between pacemaker cells known as interstitial cells of Cajal (ICCs) and between ICC and smooth muscle cells. Coupling via these junctions facilitates electrical slow-wave propagation and responses of smooth muscle to enteric motor nerves. Glycyrrhetinic acid (GA) has been shown to uncouple gap junctions, but previous studies have shown apparent nonspecific effects of GA in a variety of tissues. We tested the effects of GA using isometric force measurements, intracellular microelectrode recordings, the patch-clamp technique, and the spread of Lucifer yellow within cultured ICC networks. In murine small intestinal muscles, β-GA (10 μM) decreased phasic contractions and depolarized resting membrane potential. Preincubation of GA inhibited the spread of Lucifer yellow, increased input resistance, and decreased cell capacitance in ICC networks, suggesting that GA uncoupled ICCs. In patch-clamp experiments of isolated jejunal myocytes, GA significantly decreased L-type Ca2+ current in a dose-dependent manner without affecting the voltage dependence of this current. The IC50 for Ca2+ currents was 1.9 μM, which is lower than the concentrations used to block gap junctions. GA also significantly increased large-conductance Ca2+-activated K+ currents but decreased net delayed rectifier K+ currents, including 4-aminopyridine and tetraethylammonium-resistant currents. In conclusion, the reduction of phasic contractile activity of GI muscles by GA is likely a consequence of its inhibitory effects on gap junctions and voltage-dependent Ca2+ currents. Membrane depolarization may be a consequence of uncoupling effects of GA on gap junctions between ICCs and smooth muscles and inhibition of K+ conductances in smooth muscle cells.

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Section: Discussionmentioning

confidence: 96%

Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells

Takeda¹,

Ward²,

Sanders³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Under these conditions the expression of Cx43 by KCs, non-parenchymal cells, is enhanced to clear/repair the damage. However, the dysregulation of parenchymal versus non-parenchymal Cxs, result in alterations in the liver structure, subsequently resulting in alterations in glucose secretion, bile secretion and glycogenolysis, known to be coordinated by gap junctions and intercellular propagation of calcium waves (10,28,29). The migratory phenotype and clustering of KCs have been associated with macrophage activation, phagocytosis, debris clearance and apoptosis of macrophages and damage parenchymal cells (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

Eugenín

González

Sánchez

et al. 2007

Cellular Immunology

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Connexin43 (Cx43), a gap junction protein subunit, has been previously detected in Kupffer cells (KCs) during liver inflammation, however, KCs phagocytose cell debris that may include Cx43 protein, which could explain the detection of Cx43 in KCs. We determined that KCs express Cx43 and form gap junctions both in vivo and in vitro. In liver sections of animals treated with LPS, Cx43 was detected at ED2+ cells interfaces, indicating formation of GJ between KCs in vivo. In vitro, unstimulated KCs cultures did not form functional GJs, and expressed low levels of Cx43 that showed a diffuse intracellular distribution. In contrast, KCs treated with LPS plus IFN-γ, expressed a greater amount of Cx43 at both the, protein and mRNA levels, and showed Cx43 at cell-cell contacts associated with higher dye coupling. In conclusion, activation of KCs in vivo or in vitro resulted in enhanced Cx43 expression levels and formation of GJ that might play relevant roles during liver inflammation.

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“…Ca 2ϩ signals induced by growth factors typically have separate effects from hormone-induced Ca 2ϩ signals, although both are mediated by PLC and InsP 3 (13). In hepatocytes, for example, vasopressin activates the V 1a receptor to modulate secretion (14), glucose release (15), and apical contractility (16), whereas HGF activates c-Met to regulate cell proliferation (17). The versatility of Ca 2ϩ as a second messenger in part reflects that Ca 2ϩ signals have distinct effects in different parts of the cell (13).…”

mentioning

confidence: 99%

c-Met Must Translocate to the Nucleus to Initiate Calcium Signals

Gomes

Rodrigues

Leite

et al. 2008

Journal of Biological Chemistry

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Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca 2؉ signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin ␤1, and formation of Ca 2؉ signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus. Hepatocyte growth factor (HGF)2 is secreted by stromal cells and binds to its receptor c-Met, which is a prototypic receptor tyrosine kinase (RTK) (1). Activation of c-Met is responsible for cell proliferation under normal conditions such as tissue regeneration (2), as well as under abnormal conditions such as neoplasia (3). For example, in the liver, HGF is secreted by stellate cells and then binds to c-Met on hepatocytes (1) to mediate processes such as liver regeneration following liver resection (2) and development of hepatocellular carcinoma (4). The mechanisms of action of c-Met are not entirely understood, but it is generally believed that this and other RTKs act at the plasma membrane (5-7). However, several RTKs have been found in the nucleus, including receptors for insulin, epidermal growth factor, and fibroblast growth factor (8 -10). The function of these receptors in the nucleus is controversial (11, 12).C-met and other RTKs act in part through Ca 2ϩ signaling, which is initiated by the phospholipase C-␥ (PLC␥)/inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2ϩ signaling cascade (13). A number of peptide hormones also increase Ca 2ϩ via InsP 3 but typically do so via G protein-coupled receptors that activate PLC␤ (13). Ca 2ϩ signals induced by growth factors typically have separate effects from hormone-induced Ca 2ϩ signals, although both are mediated by PLC and InsP 3 (13). In hepatocytes, for example, vasopressin activates the V 1a receptor to modulate secretion (14), glucose release (15), and apical contractility (16), whereas HGF activates c-Met to regulate cell proliferation (17). The versatility of Ca 2ϩ as a second messenger in part reflects that Ca 2ϩ signals have distinct effects in different parts of the cell (13). Moreover, cell proliferation depends upon Ca 2ϩ signals in the nucleus rather than in the cytoplasm (18). Therefore, we examined the subcellular distribution of c-Met and the mechanism by which HGF induces c-Met to form Ca 2ϩ signals. EXPERIMENTAL PROCEDURESCells and Cell Culture-SkHep1 cells were cultured at 37°C in 5% CO 2 in Dulbecco's modified Eagle's medium (Invitrogen) containing 10% fe...

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Communication via gap junctions modulates bile secretion in the isolated perfused rat liver

Cited by 70 publications

References 26 publications

Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells

Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

c-Met Must Translocate to the Nucleus to Initiate Calcium Signals

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