Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca2+ signaling

Astrocytes represent a major target for endothelins (ETs), a family of pept ides that have potent and multiple effects on signal transduction pathways and can be released by several cell types in the brain. In the present stud y we have investigated the involvement of different ET receptor subtypes on intercellular dye diffusion, intracellular Ca2+ homeostasis, and intercell ular Ca2+ signaling in cultured rat astrocytes from hippocampus and striatu m. Depending on the ET concentration and the receptor involved, ET-1- and E T-3-induced intracellular Ca2+ increases with different response patterns. Both ET-1 and ET-3 are powerful inhibitors of gap junctional permeability a nd intercellular Ca2+ signaling. The nonselective ET receptor agonist saraf otoxin S6b and the ETB receptor-selective agonist IRL 1620 mimicked these i nhibitions. The ET-3 effects were only marginally affected by an ETA recept or antagonist but completely blocked by an ETB receptor antagonist. However , the ET-1-induced inhibition of gap junctional dye transfer and intercellu lar Ca2+ signaling was only marginally blocked by ETA or ETB receptor-selec tive antagonists but fully prevented when these antagonists were applied to gether. The ET-induced inhibition of gap junction permeability and intercel lular Ca2+ signaling indicates that important changes in the function of as troglial communication might occur when the level of ETs in the brain is in creased.