## 1 Introduction
In particular, subunits of canonical G-proteins are absent in their genomes. Moreover, it has to be clarified whether the few database entries encoding proteins with serpentine motifs might have GPCR-like functions. Instead, secondary effector proteins are present which differ considerably compared to their human counterpart. Apicomplexan adenylyl cyclase (AC) and guanylyl cyclase (GC) are bifunctional enzymes, harbouring either a putative ion channel (AC) or a P-type ATPase-like domain (GC) alongside the catalytic region [6]. Kinetoplastids contain only a single highly variable transmembrane domain and a catalytic domain, consistent with multiple receptor-activated cyclases [6]. Phosphodiesterases (PDEs) are highly conserved in the Apicomplexa and kinetoplastids but are almost insensitive to the mammalian inhibitors. PKA is a well characterized serine threonine ACG kinase in _Plasmodium_ and gains a role as a druggable target since it is essential in almost every stage of parasite development [7]. The apicomplexan PKG has structural elements and biochemical properties that distinguishes it from the human orthologues. There are four cGMP binding domains of which only three are functional [8]. Plasmodium PKG has been successfully validated by a pyrrole, the 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1\(H\)-pyrrol-3-yl]pyridine [9] and even the more effective imidazopyridines [10]. Figure 1: Comparison of a canonical, cAMP-signaling pathway in the human host cell and in Apicomplexan parasites: (**A**) Activation/reactivation cycle of a heterotrimic G-protein in the context of G-protein-coupled receptor (GPCR) signaling: 1. binding of a ligand to the receptor causing a conformational change, 2. GDP bound to the alpha-subunit is exchanged to GTP, 3. dissociation of the alpha-subunit from the G\({}_{\beta\gamma}\)-dimer and the receptor, 4. Formation of a complex between the G-alpha subunit or the G\({}_{\beta\gamma}\)-dimer and the effector molecule 5. Activation of a GTPase that hydrolyzes GTP to GDP under the control of a regulator of G-protein signaling, 6. Trimer formation of the different G-protein subunits. (**B**) Non-canonical cyclic nucleotide signaling pathways in _Plasmodium_. The exchange protein (EPAC) pathway (left side of the figure): 1. during egress and invasion of merozoites PfAC\(\beta\) triggers cAMP levels fostering the EPAC pathway which in turn leads to phosphorylation of Rap-GDP to Rap-GTP. 2. Rap-GTP activates phospholipase C (PLC) to produce inositol triphosphate (IP\({}_{3}\)) that binds to the IP\({}_{3}\) receptor. 3. Activation of the IP\({}_{3}\) receptor leads to a release of calcium ions. Calcium ions bind to calcineurinn and activate calcium-dependent protein kinase 1 (CDPK1). Middle part of the figure: besides the EPAC pathway cAMP activates protein kinase A. Right part of the figure: at low potassium concentrations an unknown ligand binds to the SR25 receptor which mediates the signal to a guanylyl cyclase that activates protein kinase G. Protein kinase G (PKG) acts in concert with a stage specific calcium dependent kinase. Moreover, apicomplexan parasites and kinetoplastids possess a set of small GTPases to infect the host cell in the absence of canonical G-proteins and putative GPCRs. Most of these small, identified GTPases belong to the Ras superfamily [11] This superfamily consists of five different classes i.e., Ras (rat sarcoma oncoproteins), Arf (ADP-ribosylation factors), Ran (Ras related nuclear GTPases), Rab (ras related proteins in brain) and Rho (Ras homologous GTPases) acting as molecular switches. Mostly represented in apicomplexan parasites and kinetoplastids are the Rab proteins controlling intracellular, vesicular transport. A variety of functions can be attributed to the Ras superfamily like the control of gene expression and cell proliferation, vesicle coating, nucleo-cytoplasmic transport and regulation of cell cycle progression.