An overview of potential drug targets in cAMP signalling pathways in trypanosomatids. Potential drug targets are highlighted as filled circles and colour coded as follows: pink, protein kinase A (PKA); red, phosphodiesterase (PDE); and dark blue, adenylyl cyclase (AC). (A) A cAMP signalling pathway in Leishmania mediates cellular adaptation and survival during hypoxia. In Leishmania major promastigotes, knockout of heme-containing AC (HemAC-Lm) under hypoxic conditions leads to increased cell death . It is unknown whether HemAC-Lm inhibition leads to cell death in mammalian-stage parasites, but it is possible that HemAC-Lm has a role in adaptation to changes in environmental oxygen in all life-cycle stages by catalysing the production of cAMP, which binds and activates PKA leading to multiple downstream effects. (B) cAMP signalling components regulate essential processes in Trypanosoma cruzi. Inhibition of PKA in epimastigotes induces cell death and is potentially implicated in immune evasion in the mammalian host by its interaction with trans-sialidases in trypomastigotes . PKA localises to both the cytosol and plasma membrane in trypomastigotes. The contractile vacuole complex (CVC) is part of the membranous spongiome network, which is essential for osmoregulation in T. cruzi. Inhibition of TcrPDEC2, which localises to the spongiome, in epimastigotes leads to dysregulation of the hyposmotic stress response , but it is unknown whether TcrPDEC2 also regulates this process in mammalian-stage parasites. (C) PDEB1 and 2 localise to the paraflagellar rod (PFR) and, when simultaneously knocked down, cell death occurs in vitro and the parasites are avirulent in mice . ESAG4 subfamily members are flagellar membrane-localised ACs that are highly expressed in bloodstream-form parasites. When the subfamily is simultaneously knocked down, cytokinesis defects occur, leading to cell death and the parasites have attenuated virulence in a mouse model .
