## 9 Cyclic Nucleotides Activate Protein Kinases A and G without Canonical G-Proteins  
The involvement of kinase cascades shows that malaria parasites are no exception in keeping these evolutionarily conserved mechanisms of signaling [109]. In _Plasmodium_, signaling can either be performed by membrane-bound adenylyl cyclase \(\beta\) mediating the signal over to the EPAC pathway involving the Ras GTPase Rap1 or directly to protein kinase A (Figure 1). Rap1 is directly activated by cAMP which leads to final activation of Calcium-dependent protein kinase 1 (CDPK1). In a different pathway, cAMP can directly activate protein kinase A. The ACG group of kinases in _Plasmodium_ comprises protein kinase A and G while a protein kinase C (PKC) is absent. The inactive PKA\({}_{\text{c}}\) enzyme is composed of a catalytic subunit c and a regulatory subunit (PKA\({}_{\text{r}}\)) with cAMP binding sites. Once cAMP is bound to PKA\({}_{\text{r}}\) it becomes inactive and PKA\({}_{\text{c}}\) can phosphorylate its substrates. In _Plasmodium_ PKA\({}_{\text{c}}\) and PKA\({}_{\text{r}}\) are encoded by single genes [110]. In contrast to mammalian PKA\({}_{\text{r}}\), the orthologue from _Plasmodium_ is missing the dimerization domain responsible for interaction with PKA activating proteins. PKA\({}_{\text{c}}\) from _Plasmodium_ acts at multiple stages during the parasite life cycle. In the asexual blood stages it is essential and sensitive to the inhibitors H89 (5-isoquinolinesulfonamide) and the PKI inhibitor peptide (l-threnyl-L-threnyl-L-threnyl-L-strosyl-L-alanyl-l-L-a-aspartyl-l-phenyllanyl-L-isoleucyl-l-alanyl-L-serylglycycl-l-arginyl-L-threnylglycycl-L-arginyl-L-aspartic acid), however to a much lesser extent than the human paraglogue. The role of PKA\({}_{\text{c}}\) in invasion of the human host cell has been demonstrated [111]. PKA\({}_{\text{c}}\) prevents increases in erythrocyte deformability [112]. Only one of the two occurring guanylyl cyclases in _Plasmodium_ is important with respect to pathogenesis, i.e., PfGC\({}_{\alpha}\) which was refractory to in vivo deletion and has a vital function in the erythrocyte blood stages [87] while early studies on the function of GC\(\beta\) revealed a role in ookinete motility and mosquito invasion [113]. Surprisingly, no pharmacological inhibitors have been identified yet although both proteins share structures which can only be found in the Apicomplexans i.e., C-terminal cyclase catalytic domains with purine in particular cGMP binding motifs and mammalian AC catalytic domains although they are functional guanylyl cyclases. Among cyclic nucleotide-regulated kinases, protein kinase G (PKG) is essential in all of the key stages of the malaria parasite life cycle. The unique structural and biochemical properties i.e., three cAMP/cGMP binding motifs, a degenerated cGMP-binding motif and a lack of leucine zipper motif for dimerization make it a \"druggable target\". Moreover, PKG is insensitive to cGMP analogues. In the absence of the nucleotide, a capping mechanism caused by a pseudo-substrate covers the active site. Mutations in these capping regions are lethal in the blood stages [9]. An imidazopyridine inhibitor [10] was identified which inhibited the unsual Thr\({}_{618}\) gatekeeper position in _Plasmodium_. Effects of the inhibitor affected gametogenesis (no rounding up of gametocytes), ookinete gliding and blood stage development (prevention of schizont rupture). Oral dosing of a _P. falciparum_ mouse model was able to clear blood-stage infection and block transmission of gametocytes to mosquitoes. A second important result is that PKG acts in concert with a stage specific calcium dependent kinase [114] (Figure 1) as in the EPAC pathway and in turn is regulating the release of calcium into the cytosol. 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 and phospholipase C and finally CDPK1.