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Secretory Portal-Porosome in Pancreatic Acinar Cells

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Secretory Portal-Porosome in Pancreatic Acinar Cells Secretory Portal-Porosome in Pancreatic Acinar Cells Bhanu P. Jena Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. e-mail: [email protected] Version 2.0, February 5th, 2021. DOI: [10.3998/panc.2021.04] I. INTRODUCTION We therefore hypothesized some 25 years ago, the presence of a tunable dial at the cell plasma Secretion is a fundamental process through which membrane for secretory vesicle docking and fusion cells communicate with their environment and without full collapse, and the generation of exchange information in a multicellular context to hydrostatic pressure within vesicles to drive reach homeostasis and sustain life. For decades, vesicular contents to the cell exterior. Through the the prevailing view was that secretion operates as use of atomic force microscope, a force an all-or-none ‘complete fusion’ event, where spectroscope, we identified nanoscale vesicles are trafficked to the cell surface to fuse transmembrane cup-shaped lipoprotein structures and completely incorporate into the plasma at the cell plasma membrane first in acinar cells of membrane. The vesicle contents then diffuse out the exocrine pancreas, and later in all cells of the cell. This hypothesis, although attractive at examined including neurons. We named the first glance, had several key setbacks. First, it structures ‘porosomes,’ that have since been predicted a quantization of secretory products implicated in a wide range of secretory events. The packaged into each secretory vesicle, when in fact, family of proteins that make up the porosome has secretory vesicle size greatly varies even within the been biochemically identified and the mesoscale same cell, sometimes as much as 6-fold. Second, structure of the complex has been well the level of additional regulation necessary to characterized through electron microscopy and rapidly and precisely internalize and sequester solution X-ray methods. Defects in one or more vesicle-associated lipids and proteins following porosome components has measurable, often incorporation into the cell plasma membrane seem highly potent effects on the regulation of secretion, extraordinarily complex, given the tens of establishing links between point mutations and thousands of different membrane lipids and their secretion-defective disease states such as differential distribution even between the same neurological disorders and cystic fibrosis that were bilayer leaflets. Third, following a secretory previously correlative and are now causative. The episode, partially empty secretory vesicles discovery of the porosome solved the conundrum accumulate within cells as observed in electron of fractional discharge of intravesicular contents micrographs (Figure 1), demonstrating that from cells by providing an explanation for regulated secretory vesicles are capable of transient fusion graded secretion. Porosomes are cup-shaped at the cell plasma membrane and incomplete or unidirectional (inside cells to the outside) transport partial content release. 2 machineries, which are supramolecular lipoprotein the cell plasma membrane, results from a structures at the cell plasma membrane ranging in “preassembled ion channel-like structure that size from 15 nm in neurons, to 100-180 nm in could open and close” (2). A later 1992 review (56) endocrine and exocrine cells and composed of opined that the principal difficulty in observing around 30-40 proteins. In comparison, the 120 nm these hypothetical pore structures, was the lack of bidirectional transport machinery, the nuclear pore ultrahigh resolution imaging tools to directly complex is composed of nearly 1,000 protein monitor their presence and study their activity in molecules. live cells. In the mid 1990’s, employing the then newly developed technique of atomic force microscopy (AFM), nanometer-scale cup-shaped pore structures and their dynamics were discovered at the apical plasma membrane in live pancreatic acinar cells (62). Circular pit-like structures containing 100-180 nm cup-shaped depressions or pores were observed at the apical plasma membrane of pancreatic acinar cells where secretion is known to occur (62). During secretion, the depression or pore openings grew larger, returning to their resting size following completion of cell secretion. Studies next established the observed depressions to be the secretory portals at the cell plasma membrane (13, 36). Following stimulation of Figure 1. Partial emptying of zymogen granules in secretion, gold-conjugated amylase antibodies acinar cells of the rat exocrine pancreas following (amylase being one of the major intra-vesicular secretion. Representative electron micrographs of enzymes secreted by pancreatic acinar cells) resting (a), and cholecystokinin-stimulated for 15 min (b) rat pancreatic acinar cells, demonstrating partial loss of accumulate at depressions. These results zymogen granule (ZG) contents following secretion. The established depressions to be the long sought- apical lumen (L) of acini demonstrating the presence of after secretory portals in cells. The study further microvilli and secreted products is observed. (c) These reported (36) the presence of t-SNAREs at the studies using electron microscopy further demonstrate that while the number of ZG remain unchanged porosome base facing the cytosol, firmly following secretion, an increase in the number of empty establishing depression structures to be secretory and partially empty vesicles are observed. Scale bar = portals where zymogen granules (ZGs) transiently 1 μm. (From reference (10)). dock and fuse for intra-vesicular content release Porosomes in the exocrine pancreas will be during secretion (36). Subsequently porosomes the major focus in this article and their dynamics at the cell plasma membrane in growth hormone (GH) secreting cells of the In 1973, the ‘transient’ or ‘kiss-and-run’ mechanism pituitary gland, and in rat chromaffin cells (15) was of secretory vesicle fusion at the cell plasma reported. In 2003, following immunoisolation of the membrane enabling fractional release of porosome structures from acinar cells of the intravesicular contents during secretion, was exocrine pancreas, its composition was proposed (7). Nearly two decades later in 1990, it determined, and isolated porosomes were was hypothesized that the fusion pore, a continuity functionally reconstituted into artificial lipid established between the vesicle membrane and membranes (42). Morphological details of 3 porosome associated with docked secretory exocrine, endocrine, and neuronal cells that vesicles were revealed using high-resolution “secretory granules are recaptured largely intact electron microscopy (42). In the past decade, following stimulated exocytosis in cultured employing a combination of approaches such as endocrine cells” (73); that “single synaptic vesicles AFM, biochemistry, electrophysiology, fuse transiently and successively without loss of conventional EM, mass spectrometry, and small identity” (3); and that “zymogen granule exocytosis angle X-Ray solution scattering analysis, this is characterized by long fusion pore openings and specialized secretory portal has been extensively preservation of vesicle lipid identity” (48, 75). The characterized and documented, and found to be past two decades have additionally witnessed present in all cells examined, including neurons much progress in our understanding of Ca2+ and (18, 37, 48). Studies (11,13,15,18,21,23,24,27- SNARE-mediated membrane fusion (4, 6, 8, 12, 29,33-38,42,48,52,59,61,62,68,74,82) establish 16, 17, 20, 22, 25, 30-32, 39, 41, 43, 53, 55, 58, porosomes to be secretory portals that perform the 60, 64, 66, 69, 70-73,79-81) and on secretory specialized task of fractional discharge of vesicle volume regulation required for precise intravesicular contents from cells during secretion. fractional release of intravesicular contents from The porosome structure and the associated cells (9, 14, 35, 40, 44, 50, 65) during secretion. transient fusion mechanism (3,73,75) These findings have greatly contributed to the accompanied by fractional discharge of vesicular progress in our understanding of porosome- contents from cells, has greatly progressed in the mediated fractional release of intravesicular past two decades. It has been demonstrated in contents from cells during secretion. Figure 2. The volume dynamics of zymogen granules (ZG) in live pancreatic acinar cells demonstrating fractional release of ZG contents during secretion. (A) Electron micrograph of pancreatic acinar cells showing the basolaterally located nucleus (N) and the apically located electron-dense vesicles, the ZGs. The apical end of the cell faces the acinar lumen (L). Bar = 2.5 µm. (B-D) Apical ends of live pancreatic acinar cells in physiological buffer imaged by AFM, showing ZGs (red and green arrowheads) lying just below the apical plasma membrane. Exposure of the cell to a secretory stimulus (1 M carbamylcholine), results in ZG swelling within 2.5 min, followed by a decrease in ZG size after 5 min. The decrease in size of ZGs after 5 min is due to the release of secretory products such as α-amylase, as demonstrated by the immunoblot assay in (E). If ZG’s had fused at the plasma membrane and fully merged, it would not be visible, demonstrating transient fusion and fractional discharge on intravesicular contents during secretion in pancreatic acinar cells. (From reference (44)). II. Porosome Discovery: AFM 25 years ago (62). This discovery was made Trained on Pancreatic Acini
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