(A, B) Schematic representation of the ErbB signaling pathway. Ligands are all produced as membrane-bound precursor proteins that are cleaved by cell-surface sheddases to yield the active growth factor species. Binding of the soluble form of the ligand induces ErbB receptor homodimerization or heterodimerization, converting the receptor to an active dimeric conformation (A). Ligands are grouped in four rows according to their receptor specificity (top; arrows); the six ligands for which ectodomain shedding is primarily mediated by ADAM17 appear in black characters, and the remaining five are in grey characters (B). (C–K) Resting CBF (C, F, I) and CBF responses to whisker stimulation (D, G, J) or topical application of adenosine (E, H, K) were evaluated before and after superfusion of various inhibitors of the ErbB signaling pathway, including the ErbB1/ErbB4 inhibitor AG1478 (10 and 20 µM); the ErbB2 inhibitor AG825 (50 and 200 µM) (C–E), the soluble ErbB receptor traps (ErbB1-Fc, 66.7 nM; ErbB3-Fc, 71.4 nM; ErbB4-Fc, 71.4 nM) and the respective control IgG1-Fc and IgG2-Fc fragments (286 nM) (F–H), heparin and the synthetic peptide p21 (12 µM) and the control inactive peptide p21-mut (12 µM) (I–K). None of these compounds affected resting CBF, except ErbB4-Fc, which produced a slight increase. (C–K) Significance was determined by one-way ANOVA followed by Tukey’s post-hoc test (*p<0.05, **p<0.01, ***p<0.001 compared to vehicle; n = 5/group). Error bars indicate SEM.