Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: Recent Progress and a Critical Assessment

Abstract

Secretory granules are located at the apex of pancreatic acinar cells. Secretagogues bind to their receptors at the basolateral membrane of acinar cells and trigger the activation of intracellular signaling pathways to elicit fusion of secretory granules with the apical plasma membrane that is followed by exocytosis of digestive pro-enzymes (the "zymogens") into the lumen. This regulated discharge of stored macromolecules is accompanied by the secretion of solutes and water to the cell exterior to hydrate these protein-rich secretory products. Previous functional and pharmacological studies in pancreatic acinar cells and zymogen granules (ZG) had suggested that ion channels and transporters are expressed in the membrane of ZG where they contribute to maturation, fusion, exocytosis and/or fluidization of zymogens. This chapter reviews studies that have been largely published in the postgenomic era and combined biochemical, immunological, electrophysiological, pharmacological, and/or occasionally knockout methodologies to identify cloned transporters and ion channels in the membrane of ZG. Available experimental evidence indicates the presence of several ion channel and transporter proteins in ZG membranes (aquaporins, vacuolar-type H + -ATPase, zinc influx transporter SLC30A2). The evidence for the K + channels Kv7.1 and Kir6.1, for ClC Cl -channels and the vesicular nucleotide transporter SLC17A9 in ZG is less strong. To better understand the function of these proteins in the secretory pathway further studies are needed. Introductory RemarksA review on the topic of pancreatic zymogen granule (ZG) channels and transporters and their function is timely as the last exhaustive review appeared in 2002 (107) and is manageable because of the limited number of publications that had been published in the 12 years since then. These circumstances have allowed me to carry out an in-depth and critical analysis of the published data. The advent of the post-genomic era had raised hopes that -similar to other areas of cell biology -a large number of ZG transport proteins would be identified and their role in pancreatic secretion would be elucidated. Indeed, recent studies have combined functional and molecular approaches to characterize ZG channels and transporters and their role in pancreas physiology. Yet, the fact that only a very limited number of studies have been published in this area of research is surprising as there have been tremendous developments of knowledge and methodologies available to investigate the molecular and cellular biology and physiology of the pancreas (122).

Protein Composition and Biogenesis of the Pancreatic Zymogen Granules

“…The evidence for the K + channels Kv7.1 and Kir6.1, for ClC Clchannels and the vesicular nucleotide transporter SLC17A9 in ZG is less strong. Detailed discussion of channels in ZG can be found in (71).…”