New anti-actin drugs in the study of the organization and function of the actin cytoskeleton

The high degree of structural and molecular complexity of the actin-based c ytoskeleton, combined with its ability to reorganize rapidly and locally in response to stimuli, and its force-generating properties, have made it, di fficult to assess how the different actin structures are assembled in cells , and how they regulate cell behavior An obvious approach to study the rela tionships between actin organization, dynamics, and functions is the specif ic perturbation of actin structures using pharmacological means. Until rece ntly there were only a few agents available that interfered with cellular a ctivities by binding to actin and most of our knowledge concerning the invo lvement of actin in basic cellular processes was based on the extensive use of the cytochalasins. In recent years we have identified an increasing num ber of actin-targeted marine natural products, including the latrunculins, jasplakinolides (jaspamides), swinholide A, misakinolide A, halichondramide s, and pectenotoxin II, which are discussed in this article. All these mari ne-sponge-derived compounds are unusual macrolides and can be classified in to several major families, each with its own distinct chemical structures. We describe the current state of knowledge concerning the actin-binding pro perties of these compounds and show that each class of drugs alters the dis tribution patterns of actin in a unique way, and that even within a chemica l class, structurally similar compounds can have different biochemical prop erties and cellular effects. We also discuss the effects of these new drugs on fenestrae formation in Liver endothelial cells as an example of their u sefulness as powerful tools to selectively unmask actin-mediated dynamic pr ocesses. (C) 1999 Wiley-Liss, Inc.