Histones and basic polypeptides activate Ca2+/cation influx in various cell types

Abstract

Histone H2A (1-10 microg/ml) added to Ehrlich ascite cell suspensions promoted: (i) Ca2+ influx, but no apparent intracellular Ca2+ mobilization; (ii) plasma-membrane depolarization and Na+ influx in Ca2+-free medium, which were recovered by Ca2+ readmission; (iii) influx of other cations such as Ba2+, Mn2+, choline+ and N-methyl-d-glucamine+, but not of propidium+, ethidium bromide and Trypan Blue. H2A-induced Ca2+ influx and cell depolarization were: (i) blocked by La3+ and Gd3+, but not by various inhibitors of receptor-activated Ca2+-influx pathways/channels; (ii) mimicked by various basic polypeptides, with Mr>4000; (iii) prevented or reversed by polyanions such as polyglutamate or heparin; (iv) present in other cell types, such as Jurkat, PC12 and Friend erythroleukaemia cells, but virtually absent from rat hepatocytes and thymocytes. We conclude that cationic proteins/polypeptides, by interacting in a cell-specific manner with the cell surface, can activate in those cells putative non-selective Ca2+ channels and membrane depolarization.

Polyamine Triggering of Exocytosis in Paramecium Involves an Extracellular Ca 2+ /(Polyvalent Cation)-Sensing Receptor, Subplasmalemmal Ca-Store Mobilization and Store-Operated Ca 2+ -Influx via Unspecific Cation Channels

“…Similar CaSR-related activities are achieved by exogenous polyamine stimulation [25,79] which also induces exocytosis in a variety of cell types, like in neuronal and in pituitary cells [87] which also contain cortical Ca stores [92]. Different types of CaSR are recognized to be widely distributed, e.g., in leukocytes, pancreatic cells or CNS neurons [11,93,100], let alone "professional" Ca 2+ -regulating cell types, like osteocytes [98,102].…”

“…Different types of CaSR are recognized to be widely distributed, e.g., in leukocytes, pancreatic cells or CNS neurons [11,93,100], let alone "professional" Ca 2+ -regulating cell types, like osteocytes [98,102]. In some systems, polyamines can directly activate different plasmalemmal channels, including Ca 2+ channels [4,25,95,97,103]. If this would apply to Paramecium, unspecific cation channels of a similar type as described by Saitow et al [84] could theoretically be directly activated by AED, even if a CaSR would not be involved.…”

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

“…Once integrated, histones induce permeabilization of membranes to cations, disruptions of cellular calcium signalling112 and cell death by necrosis. Negatively charged acute‐phase proteins (such as C‐reactive protein, CRP),14 DNA,128 innate polysaccharides (heparin)120 or synthetic macromolecules126 compete with membrane phospholipids and prevent histone integration and toxicity. Bactericidal properties of histone fragments are dependent on their ability to form amphipathic α‐helices—potentially membrane spanning domains—however no such structural analyses have been performed on mammalian cells to date 89…”

“…A number of innate and synthetic substances have demonstrated the ability to inhibit histone‐related toxicity based on surface charge alone, including plasma proteins (albumin,123 CRP14), polypeptides (polyglutamic acid126) and polysaccharides (heparin/heparanoids,111, 146 polysialic acid,147 bacterial O‐antigen148). Elevated histone‐degrading activated protein C (APC) levels are associated with better outcomes in sepsis115, 149 and trauma patients137; APC therapy is being evaluated for treatment of sepsis150 and pancreatitis 151.…”

Calcium in ciliated protozoa: Sources, regulation, and calcium-regulated cell functions

“…Such channels occur in Paramecium (Saitow et al, 1997), and they are known to mediate a SaC-type mechanism in mammalian cells (Krause et al, 1996). Another similarity is the activation of such Ca 2 + fluxes by exogenous polyamines (Williams, 1997a,b;Gamberucci et al, 1998). However, we admit that we cannot yet explain the modus operandi of the very rapid delivery of Ca 2 + (or Sr 2 +) into alveolar sacs, though any pump activity can reasonably be excluded (Section III.EA).…”