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English: CyaA is secreted from the bacterium into the calcium-containing serous fluid on mucosal surfaces through the Type I secretion system (T1SS). It binds calcium ions and co-secretionally folds into a conformation capable to bind the complement receptor 3 (CR3), known as the αMβ2 integrin, CD11b/CD18 or Mac-1, on the surface of myeloid phagocytic cells [49,50,51]. Concentration and positioning of the toxin on the surface of the cell enables its insertion into the lipid bilayer of cellular membrane. The translocation precursor of CyaA generates a path for influx of extracellular calcium ions into cells [52], which leads to activation of calpain-mediated cleavage of talin and mobilization of the CyaA–CR3 complex into lipid rafts. From there the AC domain translocates across cellular membrane into the submembrane region of cells, where signaling complexes including protein kinase A are clustered. The AC enzyme binds cytosolic calmodulin and catalyzes unregulated conversion of ATP into the key second messenger molecule 3′,5′-cyclic adenosine monophosphate (cAMP). In parallel, the RTX hemolysin part of CyaA is functionally independent of the invasive AC domain and the pore-forming precursors form oligomeric cation-selective pores that permeabilize cellular membrane for efflux of cytosolic potassium ions from cells. See parallel review by Novak et al. in this issue for further mechanistic details on CyaA action (adapted from Masin et al.).