Pancreastatin, a chromogranin A-derived peptide, inhibits transcription of the parathyroid hormone and chromogranin A genes and decreases the stability of the respective messenger ribonucleic acids in parathyroid cells in culture.

Abstract

Pancreastatin is a carboxyl-terminal amidated peptide derived from chromogranin A (CgA) corresponding to porcine CgA residues 240-288 (CgA240-288). CgA, in turn, is an acidic glycoprotein of about 450 amino acids that is costored and cosecreted with PTH in the parathyroid gland and with native hormones of many endocrine tissues. Among its effects on various endocrine glands, pancreastatin strongly inhibits the secretion of PTH and CgA by the parathyroid. The present report evaluates the action of pancreastatin on the regulation of cellular levels of PTH messenger RNA (mRNA) and CgA mRNA. After a 6-day preculture, dispersed porcine parathyroid cells were cultured for up to 48 h with or without pancreastatin in medium at stimulatory (0.5 mM) or inhibitory (3.0 mM) concentrations of Ca2+. Secretion of PTH and CgA in the absence of pancreastatin was 4- to 10-fold greater at 0.5 mM Ca2+ than at 3.0 mM Ca2+ as were the corresponding cellular levels of PTH and CgA mRNAs. Pancreastatin (10(-9)-10(-7) M) inhibited the secretion of PTH and CgA at 0.5 mM Ca2+ in a dose-dependent fashion by 93% and 75%, respectively, and decreased the cellular levels of PTH and CgA mRNAs 80% and 87%, respectively. Whereas pancreastatin inhibited the secretion of PTH and CgA by the fourth hour and beyond, changes in PTH and CgA mRNAs were not observed until 12 h. These decreases in mRNA were associated with a two-thirds reduction in the rates of transcription of the PTH and CgA genes. Additionally, the half-life of PTH mRNA decreased to 20 h from 38 h and that for CgA mRNA declined to 18 h from 33 h. It remains to be determined if the changes in transcription of the PTH and CgA genes and stability of their respective mRNAs are direct effects of pancreastatin or secondary actions due to the inhibition of secretion.