ROLE OF THE GP2 THP FAMILY OF GPI-ANCHORED PROTEINS IN MEMBRANE TRAFFICKING DURING REGULATED EXOCRINE SECRETION/

Identification and characterization of the GP2/THP family of GPI-ancho red membrane proteins associated with apical secretory membranes sugge st that this new class of GPI-linked proteins plays a critical role in regulated protein secretion and ion transport in polarized epithelial cells in pancreas, liver, lung, kidney, and gastrointestinal tract. B ased on recent information obtained from the world literature and from our own investigations we present the following two hypotheses capabl e of unifying previously diverse observations. Hypothesis 1 is that fo rmation of GP2 tetramers in the acidic milieu of the trans-Golgi netwo rk (TGN) organizes a GP2/proteoglycan (PG) matrix tightly associated w ith the luminal surface of zymogen granule (ZG) membranes, and propose s that this matrix functions in (a) membrane sorting during granule as sembly in the TGN, (b) inactivation of ZG membranes during the storage phase of secretion, and (c) regulated trafficking of ZG membranes fro m the apical plasma membrane (APM) after exocytosis. Hypothesis 2 is t hat the acinar lumen constitutes a distinct physiologic compartment fo r coupled biochemical reactions between acinar and duct cells. Because the acidic pH of the TGN plays a critical role in condensation of sec retory proteins, alkalinization of the acinar lumen is required for (a ) neutralization of the acidic pH of exocytic contents and (b) solubil ization of aggregated (pro)enzymes. Further alkalinization appears to be required for pH-dependent release of the GP2/PG matrix from the APM , a process that may regulate internalization of ZG membranes for reus e during secretion. Taken together, the two hypotheses suggest that lu minal factors including acid-base interactions and matrix assembly and disassembly processes perform critical functions during regulated sto rage and release of pancreatic (pro)enzymes. The requirement that coup ling reactions be coordinated through the actions of separate hormones [cholecystokinin (CCK) and secretin] on divergent epithelial cells (a cinar and duct cells, respectively) provides a new appreciation for th e importance of combined CCK and secretin stimulation during pancreati c secretion in response to food intake.