Schematic depiction of proposed increased activation of ERK signaling pathway in SS RBCs. Epinephrine stimulates β₂ARs on SS RBCs. β₂ARs are prototypic G-coupled receptors whose signaling is largely mediated by activation of stimulatory GTP-binding proteins (G_s proteins), and inhibited by activation of Gα_i protein. Activation of G_s proteins in turn activates AC, leading to generation of cAMP, and the subsequent activation of PKA. The activity of downstream signaling proteins, such as MEKs and ERKs is enhanced by PKA activation. The tyrosine kinase p72^Syk acts synergistically with PKA to activate MEK/ERK cascade. Activation of ERK results in phosphorylation of the ERK consensus motif on the cytoskeletal proteins α- and β-adducins, dematin, and protein 4.1, albeit not at the ERK consensus motif. Phosphorylation of cytoskeletal proteins may result in cytoplasmic membrane protein conformational changes, which could render ICAM-4 accessible to phosphorylation.