Prohormone convertase 7 is necessary for the normal processing of cholecystokinin in mouse brain

Endoproteases in the secretory pathway process pro-cholecystokinin (CCK) into the biologically active forms found in the tissues that express CCK mRNA. Thus far, the endoproteases involved in CCK processing include cathepsin L and the prohormone convertases (PC) 1, 2, and 5. This study finds that PC7 is also critical for normal production of CCK in specific areas of the brain. Loss of PC7 results in decreased levels of CCK in more brain regions than any other endoprotease studied to date. Substantial decreases in brain levels of CCK are found in the prefrontal, frontal, parietal-insular-pyriform, and temporal cortex, caudate-putamen, basal forebrain, thalamus, hippocampus, septum, and medulla of PC7 knock-out (KO) mice. A tissue-specific sexual dimorphism of PC7 activity was also identified. This is the first report that loss of PC7 alters levels of a neuropeptide in the brain. This loss of PC7 and CCK may independently contribute to the decrease in Brain Derived Neurotrophic Factor production and be partially responsible for the learning and memory defects observed in mice that lack PC7.