Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxypeptidase E-deficient, Cpe(fat)/ Cpe(fat)mice

The biosynthesis and secretion of pro-opiomelanocortin (POMC) was examined in the pituitary of Cpe(fat)/ Cpe(fat)mice, which are deficient in carboxypeptidase E, a sorting receptor for the regulated secretory pathway (Cool D R, Normant E, Shen F S, et al. Cell 1997; 83: 73-83). Dopamine inhibited forskolin-stimulated accumulation of cAMP in the intermediate lobe of Cpe(fat)/ Cpe(fat)mice, showing that their dopamine receptors were fully functional. This result indicates that the elevated, dopamine-insensitive POMC secretion previously observed in the intermediate pituitary of Cpe(fat)/ Cpe(fat)mice was constitutive, rather than due to defective dopamine receptors. Concomitant with the increase in POMC secretion was a twofold increase in POMC mRNA levels and [(35)S]-methionine incorporation into POMC. In the anterior pituitary of Cpe(fat)/ Cpe(fat)mice, a 1.6-fold increase in basal release of POMC was accompanied by a similar increase in [(35)S]-methionine incorporation into POMC, although POMC mRNA levels were unchanged. Thus, the intermediate and anterior pituitary of Cpe(fat)/ Cpe(fat)mice compensate for the constitutive secretion of POMC by upregulating biosynthesis.