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 peptides that have potent and multiple effects on signal transduction pathways and can be released by several cell types in the brain. In the present study we have investigated the involvement of different ET receptor subtypes on intercellular dye diffusion, intracellular Ca(2+) homeostasis, and intercellular Ca(2+) signaling in cultured rat astrocytes from hippocampus and striatum. Depending on the ET concentration and the receptor involved, ET-1- and ET-3-induced intracellular Ca(2+) increases with different response patterns. Both ET-1 and ET-3 are powerful inhibitors of gap junctional permeability and intercellular Ca(2+) signaling. The nonselective ET receptor agonist sarafotoxin S6b and the ET(B) receptor-selective agonist IRL 1620 mimicked these inhibitions. The ET-3 effects were only marginally affected by an ET(A) receptor antagonist but completely blocked by an ET(B) receptor antagonist. However, the ET-1-induced inhibition of gap junctional dye transfer and intercellular Ca(2+) signaling was only marginally blocked by ET(A) or ET(B) receptor-selective antagonists but fully prevented when these antagonists were applied together. The ET-induced inhibition of gap junction permeability and intercellular Ca(2+) signaling indicates that important changes in the function of astroglial communication might occur when the level of ETs in the brain is increased.