There is increasing evidence for the involvement of plasma membrane microdomains

There is increasing evidence for the involvement of plasma membrane microdomains in insulin receptor function. of vanadium compounds on lipid fluidity in erythrocyte membranes, and studies of the effects of vanadium-containing compounds on signaling events initiated by receptors known to use membrane microdomains as signaling platforms. Introduction Plasma membrane microdomains, typically small membrane regions characterized by detergent insolubility and enrichment in sphingomyelin and cholesterol [1], are increasingly associated with their ability to concentrate membrane proteins involved in transmembrane signaling. As an example of this, insulin receptors function optimally in membrane microdomains [2]. Exclusion of the insulin receptor from membrane microdomains, as seen under conditions where these is an excess of the ganglioside GM3 [3] or in Neimann-Pick disease where membrane microdomains are altered [4], produces an insulin-resistant state. This role for membrane microdomains in insulin-mediated signaling suggests a pharmacologic strategy to increase insulin responsiveness. It has been known for many years that some vanadium-containing compounds can enhance insulin responsiveness [5-10]. Determined compounds can normalize both elevated blood glucose and lipid levels and may have long-term benefits to cardiovascular health, which is a frequent complication of diabetes [11] [12]. Vanadium compounds are generally not believed to bind to the insulin receptor [13C15] and thus exert their insulin-enhancing effects downstream of the insulin receptor [10] [16C19]. However, the likely effects on multiple pathways have recently been documented in for example the DNA microarray analysis GSK343 pontent inhibitor of global gene expression levels documenting numerous changes in gene expression [16]. The possibility that vanadium compounds interact directly with membranes or proteins closely associated with GSK343 pontent inhibitor membranes seems high, particularly in light of the recent finding that the insulin-enhancing compound [VO2dipic]? (Fig. 1A) [20] [21] penetrates the lipid interface and is located in the hydrophobic GSK343 pontent inhibitor portion of the lipid layer of the microemulsion (Fig. 1C) [22] [23]. This result was unexpected considering the charge and polarity of this compound, but does support previous reports that some vanadium compounds, such as naglivan [24], are able to penetrate membrane systems [6] [25]. However, to date these studies have been carried out with different vanadium complexes, and a more exhaustive study on this topic will be forthcoming. Several classes of vanadium-compounds are Rabbit Polyclonal to MB insulin enhancing compounds and this suggests that the specific ligand is less important than the presence of vanadium within the complex. This observation is in agreement with existing literature showing that the effects of vanadium compounds vary with different oxidation state of the metal [26] [27], and that the various ligands exert a fine-tuning effect [8] [28]. Open in a separate windows Fig. 1 The structure of [VO2dipic]? (A). The structure of AOT (B). The schematic drawing of the location of [VO2dipic]? in a isooctane microsuspension and the proposed -location in the more rigid GSK343 pontent inhibitor cyclohexane system (C). The reddish circle between [VO2dipic] and AOT indicate the protons seeing each other in the NOESY spectrum (observe Fig. 2 below). The structures of cholesterol (D), decavanadate (V10) (E), BMOV (F) and [VO(saltris)]2. Here we explore the hypothesis that vanadium compounds facilitate insulin-enhancing effects through reorganization of plasma membrane lipids. These studies were motivated by the well-known insulin-enhancing properties of several lipophilic vanadium compounds [5] [6] and the fact that even a charged vanadium compound can penetrate the lipid interfacial layer in a model system [22] [23]. Although vanadium compounds are generally believed to take action downstream of the insulin receptor GSK343 pontent inhibitor [10] [16C19], some effects of these transition metal compounds may be mediated through their actions around the plasma membrane and the organization of proteins and lipids within the lipid bilayer. Thus, these insulin-enhancing vanadium compounds might evoke some effects through direct interactions with the plasma membrane of cells expressing insulin receptors. These interactions could perturb the membrane lipid business and facilitate the translocation of insulin receptors or other signaling molecules into membrane microdomains that serve as signaling platforms and, in this fashion, enhance insulin-mediated cellular responses and reduce insulin resistance. Vanadium-containing compounds affect the packing of lipids in microemulsions The negatively charged vanadium compound, dipicolinato cis-dioxovanadium(V) ([VO2dipic]? Fig. 1A, was reported to penetrate a model lipid interface. The nature of this interaction was examined in further detail in studies offered here in an AOT (Fig. 1B)/cyclohexane system which also has a negatively charged head group as the AOT/isooctane/H2O microemulsion (Fig. 1C) system previously investigated [22]. The samples used.

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