Plasma gelsolin (pGSN)
Quick links:
-> Proposed Mechanism of Action
-> General Gelsolin Information
-> Gelsolin Binding
-> pGSN Levels in Disease
-> Tissue Effects of pGSN Repletion
-> Survival Effects of pGSN Repletion
Gelsolin Binding
Gelsolin (GSN) binds both monomeric and filamentous actin, although it prefers the latter. This binding requires micromolar calcium concentrations and is very tight, with a less than nanomolar dissociation constant. When GSN binds actin filaments, it ruptures them at the binding site by breaking the noncovalent bonds holding the actin monomers together in the polymer. Following this severing reaction, GSN remains tightly bound to one end of the polarized actin filament, the so-called “barbed” end, which rapidly exchanges monomers. This “capping” effectively prevents repolymerization. Phosphoinositides have been shown to interfere with GSN’s actin depolymerization and capping and thus regulate the intracellular actin cytoskeletal remodeling.
In 2000, plasma GSN (pGSN) was shown to bind to lysophosphatidic acid (LPA; Goetzl et al. 2000; J Bio Chem 275: 14573-14578, Mintzer et al. 2006; Biochimica et Biophysica Acta 1758: 85-89, Osborn et al. 2007; Am J Physiol Cell Physiol 292: C1323-30) and to be an important mediator for a variety of physiologic processes including wound healing, neurologic development, cancer progression and angiogenesis. This finding has led to a search for other ligands that pGSN tightly binds.
In 2000, lipopolysaccharide (LPS; endotoxin) is one such additional ligand that was shown to bind to pGSN with high affinity (Bucki et al. 2005; Biochem 44: 9590-9597). Once pGSN binds LPS, the usual in vitro LPS responses are blunted including suppression of cytoskeletal actin remodeling, suppression of collagen induced platelet activation and suppression of translocation of NF-κβ in astrocytes. LPS is recognized as the component of gram negative bacteria that is responsible for the initiation of the severe systemic inflammation leading to sepsis syndrome, organ failure and death in patient infected with such bacteria. Blockade of endotoxin has been repeatedly shown to improve outcome of severe gram negative infections in animal models.
Similarly, pGSN binds lipoteichoic acid (LTA) the gram positive bacterial component responsible for the endotoxin response seen in many gram positive bacterial infections (Bucki et al. 2008; J Immunol 181: 4936-4844). Again, once bound to pGSN, the usual LTA in vitro responses are blocked including the suppression of the endothelial responses, prevention of the translocation of NF-κβ, prevention of the up-regulation of E-selectin expression, prevention of the adhesion of neutrophils and prevention of neutrophil release of IL-8.
Additionally, pGSN appears to bind endogenous lipoprotein mediators of inflammation including platelet activating factor (PAF; Osborn et al. 2007; Am J Physiol Cell Physiol 292: C1323-30).
Thus, there is accumulating evidence that pGSN binds a variety of potent lipoprotein mediators. This binding appears to block the inflammatory response of tissues to the mediators in in vitro systems as well as intact animals (see “Tissue Effects of pGSN Repletion” and see “Survival Effects of pGSN Repletion").
The binding to lipoproteins appear to be competitive with pGSN’s binding to actin. Thus, the binding of pGSN to exposed actin, such a seen in necrotic or apoptotic cells, essentially inhibits the ability of pGSN to bind and neutralize the inflammatory responses induced by these lipoproteins.
Additional evidence indicates that gelsolin tightly binds aß peptide (Chauhan et al. 1999; Biochem Biophys Res Commun 258:241-246), the pathogenic agent believed to cause Alzheimer’s disease. Up-regulation of gelsolin production in a mouse transgenic model of Alzheimer’s disease using a plasmid DNA vaccine reduces the levels of aβ (Hirko et al. 2007; Mol Therapy 15: 1623- 1629) as does IV administration of pGSN (Matsuoka et al: 2003; J Neuroscience 23: 29-33). Also aß peptide is a potent activator of blood platelets, suggesting yet another pro-inflammatory mechanism potentially blocked by pGSN.
