The anti-diabetic bis(maltolato)oxovanadium(iv) decreases lipid order while increasing insulin receptor localization in membrane microdomains

Abstract

The effects of treatment with bis(maltolato)oxovanadium(IV) (BMOV) on protein localization in membrane microdomains were investigated by comparing the effects of insulin and treatment with BMOV on the lateral motions and compartmentalization of individual insulin receptors (IR). In addition, effects of insulin and BMOV on the association of IR, phosphorylated IR (pIR) and phosphorylated insulin receptor substrate-1 (pIRS-1) with chemically-isolated plasma membrane microdomains on rat basophilic leukemia (RBL-2H3) cells were evaluated. Single particle tracking experiments indicate that individual quantum dot-labeled IR on RBL-2H3 cells exhibit relatively unrestricted lateral diffusion of approximately 1 × 10(-10) cm(2) s(-1) and are confined in approximately 475 nm diameter cell-surface membrane compartments. After treating of RBL-2H3 cells with 10 μM BMOV, IR lateral diffusion and the size of IR-containing membrane compartments is significantly reduced to 6 × 10(-11) cm(2) s(-1) and approximately 400 nm, respectively. BMOV treatment also increases the association of IR with low-density, detergent-resistant membrane fragments isolated using isopycnic sucrose-gradient centrifugation from 2.4% for untreated cells to 25.8% for cells treated with 10 μM BMOV. Additionally, confocal fluorescence microscopic imaging of live RBL-2H3 cells labeled with the phase sensitive aminonaphthylethenylpyridinium-based dye, Di-4-ANEPPDHQ, indicates that BMOV treatment, but not insulin treatment, decreases cell-surface plasma membrane lipid order while fluorescence correlation spectroscopy measurements suggest that BMOV treatment does not affect IR surface-density or insulin binding affinity. Finally, model studies using microemulsions of cetyltrimethylammonium bromide (CTAB) micelles and (1)H NMR spectroscopy show that an oxidized form of BMOV readily localizes near the CTAB head-groups at the lipid-water interface. These observations were supported by IR spectroscopic studies using microemulsions of CTAB reverse micelles showing that both BMOV and oxidized BMOV are associated with the water pool. This conclusion is based on changes in (1)H NMR chemical shifts observed for the complex, oxidized BMOV. Moreover, these shifts appeared to be informative about the location of the complex. No differences were observed in the OD absorption peak positions for the CTAB reverse micelles prepared in the presence and absence of BMOV, oxidized BMOV or maltol. Combined, these results suggest that activation of IR signaling by both insulin and BMOV treatment involves increased association of IR with specialized, nanoscale membrane microdomains. The observed insulin-like activity of BMOV or decomposition products of BMOV may be due to changes in cell-surface membrane lipid order rather than due to direct interactions with IR.

Counterion Affects Interaction with Interfaces: The Antidiabetic Drugs Metformin and Decavanadate

“…Chemical intuition might suggest that the HMet + should be penetrating the AOT interface because of chemical compatibility and Columbic attraction, and we have previously measured such an effect for other systems such as pyridine-2,6-dicarboxylic acid (dipic) [53] and metal complexes such as [VO 2 dipic] -and bis(maltolato)oxovanadium(IV) (BMOV). [20,25] NMR spectroscopic results show that the chemical shift for the HMet + methyl proton changes, which is consistent with penetration into the interface. The IR spectroscopic results show that HMet + ions significantly affect the hydrogen-bonding network present in the water pool.…”

“…How vanadium compounds are transported in biological systems is a complex topic that has been investigated by focusing both on transport by proteins in the blood as well as transport across membranes. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]28,35] The complexity of this topic is exacerbated by the aqueous oxovanadate chemistry because multiple species, nuclearities, and protonation states exist under physiological conditions. The interaction of V 10 with interfaces has been investigated in cells as well as in simple model systems such as reverse micelles (RMs) prepared from an organic solvent, water, and a surfactant.…”

“…[7][8][9][10] V 10 forms from vanadium in oxidation state +5 and is particularly stable at acidic pH. Recently, studies of how vanadium compounds interact with interface model systems and traverse membranes [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] have shown that several anionic complexes readily penetrate the interfaces, [16,17,20,21,26] but large oxometalates such as V 10 reside away from a negatively charged interface and close to a positively charged interface, as expected. [19][20][21]23,24,27,28] Because counterions can affect the properties, a suitable counterion choice could poten-By using 51 V NMR spectroscopy, we found only small differences between the metformium and Na + decavanadate materials.…”

Therapeutic properties of VO(dmpp)2 as assessed by in vitro and in vivo studies in type 2 diabetic GK rats

“…In particular, their potential insulin mimetic capacity has been extensively investigated [10][11][12][13][14][15][16]. It has been shown that VCs can be used to mitigate insufficient insulin response in DM thus presenting insulin-mimetic properties in vitro and [17][18][19][20] in vivo [21][22][23][24], and two of them were tested in clinical trials [25]. To date, the main limitation for the clinical use of VCs in the treatment of diabetes has been their potential toxicity [26].…”

A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding

“…[19][20][21][22][23] Among the several complexes exhibiting insulin enhancing properties, V IV O(maltolato) 2 (BMOV) and V IV O(ethylmaltolato) 2 (BEOV) have been extensively studied from the chemical and pharmacological points of view. 8,[21][22][23][24][25][26] Complexes with 3-hydroxy-4-pyrones (3,4-HP) have also been extensively studied. 19,[24][25][26][27][28][29] Replacement of the O atom of the pyrone ring by a N or N-R group yields pyridinone derivatives, and both families of compounds maintain the (O − , O − ) binding set, forming quite stable complexes with many metal ions.…”