Inhibition of gap junction communication in alveolar  epithelial cells by 18α-glycyrrhetinic acid

Guo, Yihe; Martinez-Williams, Cara; Gilbert, Kirk A.; Rannels, D. E.

doi:10.1152/ajplung.1999.276.6.l1018

Cited by 65 publications

(93 citation statements)

References 38 publications

(52 reference statements)

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“…In addition, our results and those of other groups indicate that connexin 43 mRNA and protein levels decrease in cells in response to 18aGCA at concentrations higher than 20 mM. 31 This raises the question about the mechanism of action of the gap junction blocker 18aGCA, which does not seem to be fully elucidated to date. We only observed minor effects on cell numbers in treated cultures.…”

Section: Discussionmentioning

confidence: 50%

The Importance of Connexin Hemichannels During Chondroprogenitor Cell Differentiation in Hydrogel Versus Microtissue Culture Models

Schrobback

Woodfield

2015

Tissue Engineering Part A

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Appropriate selection of scaffold architecture is a key challenge in cartilage tissue engineering. Gap junctionmediated intercellular contacts play important roles in precartilage condensation of mesenchymal cells. However, scaffold architecture could potentially restrict cell-cell communication and differentiation. This is particularly important when choosing the appropriate culture platform as well as scaffold-based strategy for clinical translation, that is, hydrogel or microtissues, for investigating differentiation of chondroprogenitor cells in cartilage tissue engineering. We, therefore, studied the influence of gap junction-mediated cell-cell communication on chondrogenesis of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and articular chondrocytes. Expanded human chondrocytes and BM-MSCs were either (re-) differentiated in micromass cell pellets or encapsulated as isolated cells in alginate hydrogels. Samples were treated with and without the gap junction inhibitor 18-a glycyrrhetinic acid (18aGCA). DNA and glycosaminoglycan (GAG) content and gene expression levels (collagen I/II/X, aggrecan, and connexin 43) were quantified at various time points. Protein localization was determined using immunofluorescence, and adenosine-5¢-triphosphate (ATP) was measured in conditioned media. While GAG/DNA was higher in alginate compared with pellets for chondrocytes, there were no differences in chondrogenic gene expression between culture models. Gap junction blocking reduced collagen II and extracellular ATP in all chondrocyte cultures and in BM-MSC hydrogels. However, differentiation capacity was not abolished completely by 18aGCA. Connexin 43 levels were high throughout chondrocyte cultures and peaked only later during BM-MSC differentiation, consistent with the delayed response of BM-MSCs to 18aGCA. Alginate hydrogels and microtissues are equally suited culture platforms for the chondrogenic (re-)differentiation of expanded human articular chondrocytes and BM-MSCs. Therefore, reducing direct cell-cell contacts does not affect in vitro chondrogenesis. However, blocking gap junctions compromises cell differentiation, pointing to a prominent role for hemichannel function in this process. Therefore, scaffold design strategies that promote an increasing distance between single chondroprogenitor cells do not restrict their differentiation potential in tissue-engineered constructs.

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Section: Discussionmentioning

confidence: 50%

The Importance of Connexin Hemichannels During Chondroprogenitor Cell Differentiation in Hydrogel Versus Microtissue Culture Models

Schrobback

Woodfield

2015

Tissue Engineering Part A

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“…It is known from a structural analog of Cbx, a-glycyrrhetinic acid, that its action may be weakened by the presence of serum. 32 We repeated some experiments with SLDT, which allowed to perform Cbx incubations in the presence of serum (not possible with FRAP -see Materials and Methods). Under these conditions, inhibition by Cbx was less potent (inset to Figure 4e).…”

Section: Resultsmentioning

confidence: 99%

Connexin 43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cell model

et al. 2008

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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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Inhibition of gap junction communication in alveolar epithelial cells by 18α-glycyrrhetinic acid

Cited by 65 publications

References 38 publications

The Importance of Connexin Hemichannels During Chondroprogenitor Cell Differentiation in Hydrogel Versus Microtissue Culture Models

The Importance of Connexin Hemichannels During Chondroprogenitor Cell Differentiation in Hydrogel Versus Microtissue Culture Models

Connexin 43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cell model

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

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