Abstract
Cell signaling in eukaryotes is an evolutionarily conserved mechanism to respond and adapt to various environmental changes. In general, signal sensation is mediated by a receptor which transfers the signal to a cascade of effector proteins. The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers mediating an extracellular stimulus to cyclic nucleotide-dependent kinases driving a change in cell function. In apicomplexan parasites and kinetoplastids, which are responsible for a variety of neglected, tropical diseases, unique mechanisms of cyclic nucleotide signaling are currently identified. Collectively, cyclic nucleotides seem to be essential for parasitic proliferation and differentiation. However, there is no a genomic evidence for canonical G-proteins in these parasites while small GTPases and secondary effector proteins with structural differences to host orthologues occur. Database entries encoding G-protein-coupled receptors (GPCRs) are still without functional proof. Instead, signals from the parasite trigger GPCR-mediated signaling in the host during parasite invasion and egress. The role of cyclic nucleotide signaling in the absence of G-proteins and GPCRs, with a particular focus on small GTPases in pathogenesis, is reviewed here. Due to the absence of G-proteins, apicomplexan parasites and kinetoplastids may use small GTPases or their secondary effector proteins and host canonical G-proteins during infection. Thus, the feasibility of targeting cyclic nucleotide signaling pathways in these parasites, will be an enormous challenge for the identification of selective, pharmacological inhibitors since canonical host proteins also contribute to pathogenesis.
Highlights
Protozoan parasites can be subdivided into two major groups, i.e., the Excavates with flagellar structures and the group of Alveolates which contain membranous vesicles, so called alveoli, located beneath the plasma membrane
Cycling of these GTPases occurs between an inactive GDP-bound form and an active GTP-bound form which is controlled by regulators i.e., activators like guanine nucleotide exchange factors (GEFs) and inhibitors like GTPase-activating proteins (GAPs)
These observations can be attributed to a strong interaction between immunity-related host GTPases (IRG) and rhoptry (Rob5) pseudokinases expressed by the parasite [54] having two effects: (i) prevention of oligomerization of the immunity related host GTPases (IRGs), and (ii) change in the orientation of two threonine residues that are targeted by the Toxoplasma Ser/Thr kinases, ROP17 and ROP18
Summary
Protozoan parasites can be subdivided into two major groups, i.e., the Excavates with flagellar structures and the group of Alveolates which contain membranous vesicles, so called alveoli, located beneath the plasma membrane. The cAMP signaling pathway and multiple activated factors are involved in regulating numerous physiological processes, including growth, reproduction, differentiation and apoptosis. Disruption of this pathway can lead to treatment of the disease. Research on G-protein coupled receptor (GPCR)-mediated signaling in protozoan parasites has been intensified during recent years. Depending on the sequence and the functional similarity, Gα-subunits consist of four different subfamilies [3], i.e., (Gαs, Gαi/o, Gαq and Gα 12/13). Subunits of canonical G-proteins are absent in their genomes It has to be clarified whether the few database entries encoding proteins with serpentine motifs might have GPCR-like functions.
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