Regimes of conformational transitions of a diblock polyampholyte

The conformational properties of symmetric flexible diblock polyampholytes are investigated by scaling theory and molecular dynamics simulations. The electrostatically driven coil-globule transition of a symmetric diblock polyampholyte is found to consist of three regimes identified with increasing electrostatic interaction strength. In the first (folding) regime the electrostatic attraction causes the chain to fold through the overlap of the two blocks, while each block is slightly stretched by self-repulsion. The second (weak association or scrambled egg) regime is the classical collapse of the chain into a globule dominated by the fluctuation-induced attractions between oppositely charged sections of the chain. The structure of the formed globule can be represented as a dense packing of the charged chain sections (electrostatic attraction blobs). The third (strong association or ion binding) regime starts with direct binding of oppositely charged monomers (dipole formation), followed by a cascade of multipole formation (quadrupole, hexapole, octupole, etc.), leading to multiplets analogous to those found in ionomers. The existence of the multiplet cascade has also been confirmed in the simulations of solutions of short polymers with only one single charge (either positive or negative) in the middle of each chain. We use scaling theory to estimate the average chain size and the electrostatic correlation length as functions of the chain length, strength of electrostatic interactions, charge fraction, and solvent quality. The theoretically predicted scaling laws of these conformational properties are in very good agreement with our simulation results.

Using U0126 to dissect the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in the regulation of gene expression by endothelin-1 in cardiac myocytes

The hypertrophic agonist endothelin-1 rapidly but transiently activates the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade (and other signalling pathways) in cardiac myocytes, but the events linking this to hypertrophy are not understood. Using Affymetrix rat U34A microarrays, we identified the short-term (2-4 h) changes in gene expression induced in neonatal myocytes by endothelin-1 alone or in combination with the ERK1/2 cascade inhibitor, U0126. Expression of 15 genes was significantly changed by U0126 alone, and expression of an additional 78 genes was significantly changed by endothelin-1. Of the genes upregulated by U0126, four are classically induced through the aryl hydrocarbon receptor (AhR) by dioxins suggesting that U0126 activates the xenobiotic response element in cardiac myocytes potentially independently of effects on ERK1/2 signalling. The 78 genes showing altered expression with endothelin-1 formed five clusters: (i) three clusters showing upregulation by endothelin-1 according to time course (4 h > 2 h; 2 h > 4 h; 2 h approximately 4 h) with at least partial inhibition by U0126; (ii) a cluster of 11 genes upregulated by endothelin-1 but unaffected by U0126 suggesting regulation through signalling pathways other than ERK1/2; (iii) a cluster of six genes downregulated by endothelin-1 with attenuation by U0126. Thus, U0126 apparently activates the AhR in cardiac myocytes (which must be taken into account in protracted studies), but careful analysis allows identification of genes potentially regulated acutely via the ERK1/2 cascade. Our data suggest that the majority of changes in gene expression induced by endothelin-1 are mediated by the ERK1/2 cascade.