The membrane-permeable calmodulin inhibitors (W-7/W-13) bind to membranes changing the electrostatic surface potential. Dual effect of W-13 on EGFR activation

Membrane-permeable calmodulin inhibitors, such as the napthalenesulfonamide derivatives W-7/W-13, trifluoperazine, and calmidazolium, are used widely to investigate the role of calcium/calmodulin (Ca2+/CaM) in living cells. If two chemically different inhibitors (e.g. W-7 and trifluoperazine) produce similar effects, investigators often assume the effects are due to CaM inhibition. Zeta potential measurements, however, show that these amphipathic weak bases bind to phospholipid vesicles at the same concentrations as they inhibit Ca 2 /CaM; this suggests that they also bind to the inner leaflet of the plasma membrane, reducing its negative electrostatic surface potential. This change will cause electrostatically bound clusters of basic residues on peripheral (e.g. Src and K-Ras4B) and integral (e.g. epidermal growth factor receptor (EGFR)) proteins to translocate from the membrane to the cytoplasm. We measured inhibitor-mediated translocation of a simple basic peptide corresponding to the calmodulin-binding juxtamembrane region of the EGFR on model membranes; W-7/W-13 causes translocation of this peptide from membrane to solution, suggesting that caution must be exercised when interpreting the results obtained with these inhibitors in living cells. We present evidence that they exert dual effects on autophosphorylation of EGFR;W-13 inhibits epidermal growth factordependent EGFR autophosphorylation under different experimental conditions, but in the absence of epidermal growth factor, W-13 stimulates autophosphorylation of the receptor in four different cell types. Our interpretation is that the former effect is due toW-13inhibition of Ca 2 /CaM, but thelatter results could be due to binding of W-13 to the plasma membrane.

Superconducting p-branes and extremal black holes

In Einstein-Maxwell theory, magnetic flux lines are "expelled" from a black hole as extremality is approached, in the sense that the component of the field strength normal to the horizon goes to zero. Thus, extremal black holes are found to exhibit the sort of ¿Meissner effect¿ which is characteristic of superconducting media. We review some of the evidence for this effect and present new evidence for it using recently found black hole solutions in string theory and Kaluza-Klein theory. We also present some new solutions, which arise naturally in string theory, which are non-superconducting extremal black holes. We present a nice geometrical interpretation of these effects derived by looking carefully at the higher dimensional configurations from which the lower dimensional black hole solutions are obtained. We show that other extremal solitonic objects in string theory (such as p-branes) can also display superconducting properties. In particular, we argue that the relativistic London equation will hold on the world volume of ¿light¿ superconducting p-branes (which are embedded in flat space), and that minimally coupled zero modes will propagate in the adS factor of the near-horizon geometries of "heavy," or gravitating, superconducting p-branes.