Cholecystokinin octa- and tetrapeptide degradation by synaptic membranes. II. Solubilization and separation of membrane-bound CCK-8 cleaving enzymes

Differential Inhibition of Aminopeptidase A and Aminopeptidase N by New .beta.-Amino Thiols

“…4 The relative physiological importance of peptides issued from angiotensin I processing in the central nervous system is controversial, but there is increasing evidence that angiotensin I11 is a crucial component of the brain renin angiotensin s y~t e m .~~~-~ However, in peptidergic cascades, where different peptidases sequentially release different putative active ligands from a single inactive precursor, the key to analyzing the various steps is to possess highly specific and potent inhibitors of each enzyme. The pharmacological responses measured in the presence of selective inhibitors can then be unequivocally related to the physiological action of tonically released peptides, as demonstrated for the opioid peptides, enkephalins, and the atrial natriuretic peptide (for a review, see ref 10).…”

“…Aminopeptidase A (APA, glutamyl aminopeptidase, EC 3.4.11.7) is thought to be responsible for the transformation of angiotensin II to angiotensin III, by hydrolyzing its N-terminal aspartyl residue.1•2 The enzyme is highly selective for acidic amino acids3 and is also probably involved in the metabolism of other peptides containing an N-terminal Asp or Glu residue, such as CCKe•4•5 Aminopeptidase N (APN, EC 3.4.11.2) seems to be the enzyme that inactivates angiotensin III, by cleaving its N-terminal arginyl residue,6 and has been proposed to sequentially degrade CCK7. 4 The relative physiological importance of peptides issued from angiotensin I processing in the central nervous system is controversial, but there is increasing evidence that angiotensin III is a crucial component of the brain renin angiotensin system.2•7-9 However, in peptidergic cascades, where different peptidases sequentially release different putative active ligands from a single inactive precursor, the key to analyzing the various steps is to possess highly specific and potent inhibitors of each enzyme. The pharmacological responses measured in the presence of selective inhibitors can then be unequivocally related to the physiological action of tonically released peptides, as demonstrated for the opioid peptides, enkephalins, and the atrial natriuretic peptide (for a review, see ref 10).…”

Gastrin, cholecystokinin and gastrointestinal tract functions in mammals

“…This indirect mechanism agrees with the facts that amylase release from human pancreatic acinar cells is not mediated by either the CCK 1 or CCK 2 receptor in vitro (Miyasaka et al 2002) and that the administration of antagonists of the CCK 2 receptor does not totally inhibit the in vivo pancreatic response to a meal in the pig (Lhoste et al 2002). Moreover, if we consider the classic hypothesis of hormonal action of CCK via the blood, we must keep in mind, first, that the blood plasma contains enzymes, endopeptidases and aminopeptidases, capable of deactivating CCK (Deschodt-Lanckman et al 1983), and second, that the intestinal blood promptly transports these newly released gut peptides to the liver, an important site of gut peptide deactivation. It seems unlikely, therefore, that a message precisely generated in response to food or other local stimuli in the upper gut would be arbitrarily modified in the first pass by the liver and blood plasma enzymes well before reaching the exocrine pancreas.…”

A serine peptidase responsible for the inactivation of endogenous cholecystokinin in brain.

“…Several studies have shown that ill-characterized acidic (13,14) or neutral aminopeptidases (13), enkephalinase (EC 3.4.24.11) (15)(16)(17), a thiol-endopeptidase (18) or a metallo-endopeptidase (19) may participate in the hydrolysis of exogenous by cerebral membranes, with cleavages occurring at various peptide bonds within the molecule. However, numerous peptidases capable of hydrolyzing neuropeptides are present in cerebral membranes, and metabolic pathways of exogenous neuropeptides may not reliably reflect those responsible for endogenous neuropeptide inactivation, as illustrated in the case of enkephalins' (1)(2)(3)(4)(5).…”