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Evidence that the Peripheral‐Type Benzodiazepine Receptor Ligand Ro 5–4864 Inhibits β‐Endorphin Release from AtT‐20 Cells by Blockade of Voltage‐Dependent Calcium Channels
Author(s) -
Bisserbe J. C.,
Patel J.,
Eskay R. L.
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00774.x
Subject(s) - forskolin , gabaa receptor , medicine , endocrinology , chemistry , receptor , biology , microbiology and biotechnology , biochemistry
The demonstrations that Ro 5–4864, a ligand selective for the peripheral‐type benzodiazepine (BZD) binding site, inhibited cellular differentiation and proliferation and that occupancy of the peripheral‐type BZD binding site likely mediated the observed BZD effects on diverse endocrine tissues suggested that Ro 5–4864 disrupted a common cellular regulatory event. Using a well‐characterized anterior pituitary‐derived tumor cell line (AtT‐20 cells), which synthesizes and secretes adrenocorticotropic hormone (ACTH), β‐lipotropin hormone (β‐LPH), and β‐endorphin (BE), we have investigated the molecular mechanism of action of Ro 5–4864's capacity to alter BE secretion. Ro 5–4864 inhibits basal and induced BE release from AtT‐20 cells, through a cyclic AMP‐independent mechanism. Ro 5–4864 completely blocked the corticotropin‐releasing hormone and forskolin‐induced release of BE without altering the concomitant production of cyclic AMP. The addition to AtT‐20 cells of CGP 28392, a dihydropyridine that has been demonstrated in other systems to specifically activate by increasing concentrations of Ro 5–4864. In contrast to the capacity of Ro 5–4864 to block CGP‐induced BE release, Ro 5–4864 lacked the capacity to block enhanced BE secretion due to the calcium ionophore A23187, which increases intracellular Ca 2+ levels independent of the voltage‐dependent Ca 2+ channels. Our findings suggest that Ro 5–4864 inhibits BE secretion from AtT‐20 cells through a blockade of the voltage‐dependent membrane Ca 2+ channels and this mechanism of action may be responsible for Ro 5–4864's diverse effects observed on other cell types.