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Regulated Secretion and Microfilaments

Page updated 13/11/02

Many cell types synthesize secretory products and store them in vesicles to be released upon stimulation with a relevant chemical or electrical signal.  This is known as stimulus-dependent, or regulated secretion. A dense network of actin filaments lies both between individual vesicles and between the vesicle population and the plasma-membrane and so there is a problem of how the cell is able to rapidly disassemble the microfilament network to permit the vesicles to fuse with each other and the plasma membrane during secretion (Puszkin et al, 1976; Meyer & Burger, 1979; Burgoyne & Cheek, 1987).

It has been suggested that the vesicles formed in the cell body travel to cellular extremities via molecular motors (e.g. kinesin, myosin1) and are prevented from diffusing from these sites by entanglement in a web of microfilaments.  Several studies have shown that secretory vesicles are surrounded by a dense web of actin filaments (Puszkin et al, 1976; Meyer & Burger, 1979) which also separates the vesicles from the plasma membrane.  It has been suggested that an actin filament severing protein “scinderin” is responsible for removing filaments underlying the plasma membrane (Trifaró et al, 1993), and while this may well be the case, it is likely that other severing proteins such as the ADF/Cofilins, are responsible for the rapid depolymerisation of the same filaments and in addition of filaments deeper within the cell, between the vesicles.  In a variety of cell types, exocytosis is potentiated by the disruption of microfilaments (Lelkes et al, 1986; Sontag et al, 1988; Muallem et al, 1995; Borovikov et al, 1995), and is inhibited by agents which stabilise microfilaments (Lelkes et al, 1986; Castellino et al, 1992).  The situation is more complex than this however as role of actin filaments in regulated secretion is not only inhibitory, Low concentrations of actin filament disrupting agents caused a stimulation of exocytosis when added to streptolysin-O permeabilised pancreatic acinar cells, yet higher concentrations of these agents inhibited secretion (Muallem et al, 1995).  This suggests that a minimal actin cytoskeleton is necessary for regulated exocytosis, in agreement with the finding that actin depolymerises from the cortex but re-polymerises deeper within the cell (Norman et al, 1994).  It is possible that the cofilins have properties which would allow them to sever filaments immediately on receipt of a secretory signal, and to allow re-polymerization of actin later in the secretion event.

 The role of Myosin II

(Spudich 1994)



Borovikov, Y.S., Norman, J.C., Price, L.S., Weeds, A. and Koffer, A.  (1995). Secretion from permeabilised mast cells is enhanced by addition of gelsolin:  contrasting effects of  endogenous gelsolin.  J.Cell Sci.  108  657-666.

Burgoyne, R.D. and Cheek, T.R. (1987).  Reorganisation of peripheral actin filaments as a prelude   to exocytosis.  Bioscience Rep.  7  281-288.

Castellino, F., Heuser, J., Marchetti, S., Bruno, B. and Luini, A.  (1992). Glucucorticoid stabilization of actin filaments: A possible mechanism for inhibition of corticotropin release. Proc.Nat.Acad.Sci. USA.  89  3775-3779.

Chamberlain, L.H., Roth, D., Morgan, A., and Burgoyne, R.D.  (1995).  Distinct effects of a- SNAP, 14-3-3 proteins, and calmodulin on priming and triggering of regulated exocytosis. J.Cell Biol.  130 1063-1970.

Davidson, M.M.L. and Haslam, R.J. (1994). Dephosphorylation of cofilin in stimulated platelets: roles for a GTP-binding protein and Ca2+.  Biochem. J.  301  41-47.

Heuser, J. (1989). Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH.  J.Cell Biol.  108  855-864.

Ishikawa, R., Yamashiro, S., and Matsumura, F.  (1989).  Differential modulation of actin-severing activity of gelsolin by multiple isoforms of cultured rat cell tropomyosin. J.Biol.Chem.  264  7490-7497.

Kanamori, T., Hayakawa, T., Suzuki, M. and Titani, K.  (1995). Identification of two 17- kDa rat parotid gland phosphoproteins, subjects for dephosphotylation upon b-adrenergic stimulation, as destrin- and cofilin-like proteins.  J.Biol.Chem.  270  8061-8067.

Koffer, A. and Gomperts, B.D.  (1989).  Soluble proteins as modulators of the exocytotic reaction of permeabilised rat mast cells.  J.Cell Sci.  94  585-591.

Lelkes, P.I., Friedman, J.E., Rosenheck, K., and Oplatka, A. (1986). Destabilization of actin filaments as requirement for the secretion of catecholamines from permeabilized chromaffin  cells. FEBS letters  208  357-363.

Marcu, M. G., Zhang, L., Naustaudt, K. & Trifaro, J. M. (1996) Recombinant scinderin, an F-actin severing protein, increases calcium-induced release of serotonin from permeabilized platelets, an effect blocked by 2 scinderin-derived actin-binding peptides and phosphatidylinositol 4,5-bisphosphate. Blood. 87, 20-24.

Meyer, D.I., Burger, M.M. (1979). The chromaffin granule surface: the presence of actin and the nature of its interaction with the membrane.  FEBS letters 101  129-133.

Mochida, S., Kobayashi, H., Matsuda, Y., Yuda, Y., Muramoto, K. and Nonomura, Y. (1994). Myosin II is involved in transmitter release at synapses formed between rat sympathetic neurons in culture.  Neuron  13  1131-1142.

Morgan, A. and Burgoyne, R.D. (1995).  A role for soluble NSF attachment proteins (SNAPs) in regulated exocytosis in adrenal chromaffin cells.  EMBO J.  14  232-239.

Morgan, T.E, R.O. Lockerbie, L.S. Minamide, M.D. Browning and Bamburg, J.R. (1993). Isolation and characterization of a regulated form of actin depolymerizing factor.  J.Cell Biol.  122 623-633. 

Muallem, S., Kwiatkowska, K., Xu, X. and.Yin, H.L.  (1995). Actin filament disassembly is a sufficient final trigger for exocytosis in nonexcitable cells.  J.Cell Biol.  128  589-598.

Puszkin, S., Kochwa, S. and Rosenfield, R.E. (1976). Ultrastructural evidence of association of contractile proteins in synaptosomes. in “Cell Motility” Eds. Goldman, R., Pollard, T. and  Rosenbaum, J. Cold Spring Harbor Conferences on Cell proliferation Volume 3. 

Rodriquez Del Castillo, A., Vitale, M.L. and Trifaro, J.-M. (1992).  Ca2+ and pH determine the interaction of chromaffin cell scinderin with phosphatidylserine and phosphatidylinositol 4,5, -bisphosphate and its cellular distribution during nicotinic-receptor stimulation and protein kinase C activation.  J.Cell Biol.  119  797-810.

Rosario, L., Strutzin, A., Cragoe, E.J., and Pollard, H.B.  (1991).  Modulation of intracellular pH by secretagogues and by the Na+/H+ antiporter in cultured bovine chromaffin cells. Neuroscience 41  269-276.

Saito, T., Lamy, F., Roger, P.P., Lecocq, R., and Dumont, J.E.  (1994). Characterization and  identification as cofilin and destrin of 2 thyrotropin-regulated and phorbol ester-regulated phosphoproteins in thyroid-cells. Exp.Cell Res. 212  49-61.

Sontag, J.M., Aunis, D., and Bader, M.F. (1988). Peripheral actin filaments control calcium- mediated catecholamine release from streptolysin-O permeabilized chromaffin cells. Eur.J.Cell Biol.  46  316-326.

Spudich, A. (1994).  Myosin reorganization in activated RBL cells correlates temporally with stimulated secretion. Cell Mot.Cytoskel.  29  345-353.

Stella, N., Pellerin, L.and Magistretti, P.J. (1995).  Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: Involvement of a pH-sensitive membrane phospholipase A2.  J.Neuroscience  15  3307-3317.

Trifaró, J. M., Vitale, M. L. & Delcastillo, A. R. (1993) Scinderin and chromaffin cell actin network dynamics during neurotransmitter release. J.Physiology-paris. 87, 89-106.

Vitale, M.L., Seward, E.P., and Trifaro, J.-M. (1995).  Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis. Neuron  14  353-363.

Yamashiro, S. and Matsumura, F. (1991).  Mitosis-specific phosphorylation of caldesmon: Possible molecular mechanism of cell rounding during mitosis.  BioEssays 13  563-568. 

Zhang, L., Marcu, M. G., Naustaudt, K. & Trifaro, J. M. (1996) Recombinant scinderin enhances exocytosis, an effect blocked by 2 scinderin-derived actin-binding peptides and PIP2. Neuron. 17, 287-296.

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