Arachidonic acid-induced dye uncoupling in rat cortical astrocytes is mediated by arachidonic acid byproducts

doi:10.1016/S0006-8993(98)01016-6

Brain Research

Volume 816, Issue 2, 23 January 1999, Pages 411-423

https://doi.org/10.1016/S0006-8993(98)01016-6 Get rights and content

Abstract

Arachidonic acid (AA) induced a concentration- and time-dependent reduction in gap junction-mediated dye coupling between cultured astrocytes. The effect was greatly diminished by inhibition of cyclooxygenases and lipoxygenases. The action of a low concentration of AA (5 μM) was also prevented by Ca²⁺-free extracellular solution or a high concentration of melatonin, a potent free radical scavenger, but not by Nω-nitro-l-arginine, a nitric oxide (NO) synthase inhibitor. Thus, this effect may depend on Ca²⁺ influx and oxygen free radicals but not on NO generation. Cellular uncoupling induced by a high (100 μM), but not a low, AA concentration was rapidly reversed by washing with albumin containing solution. After reversal from 5 min but not 2.5 min inhibition with a high AA concentration dye coupling between astrocytes became refractory to a low concentration of AA, suggesting desensitization of the response elicited by a low concentration of the fatty acid. Dye uncoupling occurred without changes in levels and state of phosphorylation (immunoblotting and $^{32} P$ -incorporation) of connexin43, the main astrocyte gap junctional protein. However, maximal cell uncoupling induced by a low (Slow action) but not by a high (Fast action) AA concentration was paralleled by a reduction in connexin43 (immunofluorescence) at cell-to-cell contacts. It is proposed that the AA-induced dye uncoupling is mediated by byproducts that induce rapid channel closure or slow removal of connexin43 gap junctions.

Introduction

Cortical astrocytes couple to each other, both in vivo and in vitro, by numerous gap junctions which confer them a functional syncytial organization 22, 34, 37. Gap junction channels permit the intercellular exchange of current-carrying ions (e.g., K⁺), second-messenger molecules (e.g., cyclic nucleotides, Ca²⁺, inositol 1,4,5-trisphosphate) and various metabolites 4, 9. Consequently, astrocyte gap junctions are believed to create a buffering system that is responsible for the dissipation of focal extracellular K⁺ and neurotransmitter concentration increases resulting from intense neural activity 39, 48, 49. Therefore, gap junctional communication between astrocytes facilitates the normal functioning of neurons and protects them from excitotoxicity of neurotransmitters. In agreement, it has been recently reported that astrocytic gap junctional communication decreases neuronal vulnerability to a cell insult [7]. Moreover, gap junctions mediate the propagation of calcium waves between astrocytes after receptor 12, 13, 29, 70or mechanic stimulation [11], providing an extraneuronal cell-to-cell signaling pathway.

Gap junction channels span the plasma membrane of two adjacent cells. The contribution of each cell is termed an hemichannel or connexon, each of which is constituted of six protein subunits called connexins. At least 14 rodent connexins have been cloned from various tissues and each one is named according to its molecular mass predicted from the cloned DNA sequence (e.g., the 43–45 kDa protein with a predicted molecular mass of 43-kDa found in heart gap junctions is called connexin43, Cx43) [6]. Studies in primary cultures of brain astrocytes 17, 27have shown that Cx43 is the major gap junction channel protein in astrocytes.

The activation of astrocytic receptors by endogenous ligands, including norepinephrine [28], glutamic acid [21], and endothelins [68], affects the degree of coupling between adjoining cells. Consequently, the functional state of gap junction channels can be modulated by cyclic AMP, Ca²⁺ and diacylglycerol-dependent pathways 4, 9; the receptor-mediated alterations may use these second messengers. Moreover, two diffusible neurotransmitters, nitric oxide (NO) 8, 54and arachidonic acid (AA) 28, 69and its derivative anandamide [69], have been shown to reduce gap junctional communication between astrocytes. Nonetheless, their mechanism of action remains largely unknown.

The AA is a fatty acid that directly affects the functional state of various molecules, including the protein kinase C (PKC) [42], calcium channels [45]and (Na⁺/K⁺)-ATPase [64]. Moreover, various biologically active products are yielded through its metabolism via a cyclooxygenase-dependent pathway forming prostaglandins and thromboxanes, and a lipoxygenase-dependent pathway generating leukotrienes, lipoxins, and related compounds [60]. Several of these compounds affect the functional state of a variety of membrane proteins, including plasma membrane Ca²⁺ and K⁺ channels 38, 51, 58, 60and the Na⁺/Ca²⁺ exchanger [50], as well as second messenger pathways 14, 15, 30, 35. Moreover, metabolites of AA, such as prostaglandin D₂ increase the activity of NO synthase [71], suggesting a link between AA metabolism and NO synthesis. Other AA byproducts generated by cyclooxygenase and lipoxygenase-dependent pathways are oxygen free radicals which are highly reactive compounds that affect a variety of cell functions [61].

Gap junctions between hepatocytes 52, 55, cells of lacrimal glands [26], neonatal cardiac myocytes 23, 43, 67, a rat mammary tumor cell line [74], Novikoff cells [41], and retinal horizontal cells [44]are also blocked by AA. While gap junction inhibition in lacrimal cells has been proposed to occur by direct interaction of AA on the channels [26], in others systems the effect seems to be mediated, at least in part, by byproducts of the AA metabolism 23, 43, 52, 55. It is unknown whether astrocyte uncoupling is induced directly by AA or indirectly by its metabolites.

The present work was undertaken to elucidate possible mechanisms that could explain the AA-induced reduction in dye coupling in primary cultures of rat cortical astrocytes. It was found that AA induced a profound reduction in gap junctional communication between astrocytes in a manner independent of NO generation, but dependent on AA metabolism through cyclooxygenases and lipoxygenases. The AA-induced astrocyte uncoupling was not correlated with changes in levels or state of phosphorylation of Cx43. Both high and low concentrations of AA induced similar maximal effects but with different time courses and through different mechanisms.

Section snippets

Reagents

Arachidonic acid, melatonin, Nω-nitro-l-arginine, indomethacin, nordehydroguaiaretic acid (NDGA), 1,3-dimethyl-2-thiourea (DMTU), phorbol 12-myristate 13 acetate (PMA), phenylmethylsulfonyl fluoride (PMSF), dimethyl sulfoxide, and Lucifer yellow were purchased from Sigma (St. Louis, MO, USA). Luzindole was from Alexis (San Diego, CA, USA). F-12 medium, minimal essential medium (MEM), fetal bovine serum, horse serum, penicillin, trypsin-EDTA, bovine pancreas DNAase I and streptomycin were from

AA induces a dose and time-dependent reduction in dye coupling

In confluent cultures, astrocytes were coupled to an average of 15±3 cells (Fig. 1A) and the incidence of dye coupling was 100%. In 6 out of 12 experiments, the initial dye uncoupling response after the addition of 5 μM AA was quite heterogeneous; a few minutes (5 min) after the addition of the fatty acid, 15–25% of the cells were completely uncoupled, while the others still showed a normal degree of communication with neighboring cells. In the other six experiments, the reduction in dye

Discussion

In the present work, we studied the possible mechanism of action of AA-induced inhibition of astrocyte gap junctional communication. We found that uncoupling of astrocytes was mediated by products generated in AA cyclooxygenase and lipoxygenase metabolic pathways, which predominantly produced either a rapid closure of gap junction channels or a slow cellular redistribution of the main channel forming protein, Cx43.

Using the dye coupling technique, we found that a high AA concentration (100 μM)

Acknowledgements

The authors thank Dr. M.V.L. Bennett for his suggestions. This work was partially supported by Fondecyt grants 2960001 (to A.D.M.) and 1960559 (to J.C.S.). The data in this paper are from a thesis to be submitted in partial fulfillment of the requirements for the Degree of Doctor in Sciences (A.D. Martı́nez) in the Pontificia Universidad Católica de Chile.

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Research reportArachidonic acid-induced dye uncoupling in rat cortical astrocytes is mediated by arachidonic acid byproducts

Abstract

Introduction

Section snippets

Reagents

AA induces a dose and time-dependent reduction in dye coupling

Discussion

Acknowledgements

Neuron

Neuron

Cell Calcium

J. Biol. Chem.

TIPS

Brain Res.

Neuron

Trends Neurosci.

Life Sciences

Brain Res.

J. Mol. Cell. Cardiol.

Biochem. Pharmacol.

Biophys. J.

Neuroscience

J. Bull. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Prog. Cell Res.

Toxicol. Appl. Pharmacol.

Lactic acid inhibition of gap junctional intercellular communication in in vitro astrocytes as measured by fluorescence recovery after laser photobleaching

Glia

Differential down-regulation of protein kinase C subspecies in KM3 cells

FEBS Lett.

Effect of dimethylthioures in hyperoxic injury

J. Lab. Clin. Med.

On the mechanism of cell uncoupling induced by a tumor promoter phorbol ester in clone 9 cells, a rat liver epithelial cell line

Eur. J. Cell Biol.

Connexin43: a protein from rat heart homologous to a gap junction protein from liver

J. Cell Biol.

Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death

J. Neurochem.

Induction of nitric oxide synthase inhibits gap junction permeability in cultured rat astrocytes

J. Neurochem.

Connections with connexins: the molecular basis of direct intercellular signaling

Eur. J. Biochem.

Inhibition of lipoperoxidation of linoleic acid by five antioxidants of different lipophilicity

Pharmazie

Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling

Science

Modulation of Ca2+ cycling in cardiac myocytes by arachidonic acid

Circ. Res.

Arachidonic acid enhances contraction and intracellular Ca2+ transients in individual rat ventricular myocytes

Am. J. Physiol.

Gap junctions between cultured astrocytes: immunocytochemical, molecular, and electrophysiological analysis

J. Neurosci.

Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury

J. Neurochem.

Activation of protein kinase C blocks astroglial gap junction communication and inhibits the spread of calcium waves

J. Neurochem.

Astroglial gap junction communication is increased by treatment with either glutamate or high K+ concentration

J. Neurochem.

Cultured astrocytes form a syncytium after maturation

Exp. Cell Res.

Effects of arachidonic acid on the gap junctions of neonatal rat heart cells

Pflügers Arch.

Research report
Arachidonic acid-induced dye uncoupling in rat cortical astrocytes is mediated by arachidonic acid byproducts

Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca²⁺ homeostasis and cell death

Modulation of Ca²⁺ cycling in cardiac myocytes by arachidonic acid

Arachidonic acid enhances contraction and intracellular Ca²⁺ transients in individual rat ventricular myocytes

Astroglial gap junction communication is increased by treatment with either glutamate or high K⁺ concentration