Expression of a functional endothelin (ET(A)) receptor in human meningiomas

Endothelin (ET) receptor subtypes (ET(A) and ET(B)) in human meningiomas were characterized using quantitative receptor autoradiography. A single class of high-affinity I-ET-1 binding sites was localized in all meningioma tissue studied (dissociation constant: 2.4 ± 0.3 nM, maximum binding capacity: 319 ± 66 fmol/mg (mean ± standard error of the mean for 13 tumors)). Unlabeled ET-1 showed a strong affinity for I-ET-1 binding to tissue sections of the tumors with a 50% inhibiting concentration (IC) of 2.9 ± 0.7 x 10 M, whereas ET-3 showed a much lower affinity (IC: 8.4 ± 2.5 x 10 M). Sarafotoxin S6c, a selective agonist for the ET(B) receptor, could not compete for I-ET-1 binding to meningiomas. Endothelin-1 significantly stimulated deoxyribonucleic acid (DNA) synthesis in a dose-dependent manner in cultured human meningioma cells. In contrast, no significant stimulation of DNA synthesis occurred with an S6c concentration up to 10 M. Pretreatment of the meningioma cells with pertussis toxin, a bacterial toxin that adds adenosine 5'-diphosphate-ribose to the α subunit of guanine nucleotide binding (G) proteins such as G(i) or G(o), induced a concentration-dependent reduction in ET-stimulated DNA synthesis in meningioma cells, but did not affect the epidermal growth factor-induced DNA synthesis. These observations suggest that the ET(A) receptor is predominantly expressed in human meningioma tissue and that ET may act as a growth factor on the meningioma cells by interacting with the ET(A) receptor and by pertussis toxin-sensitive mechanisms.