## 1 Introduction
### Non Canonical G-Proteins and Putative GPCRs in Plasmodium  
Research on GPCR-mediated signaling pathways in _Plasmodium_ has just started over the last decade. During infection the malaria parasite has to adapt to different environmental changes in the human host i.e., the pre-erythrocytic stage in the human liver and the erythrocyte blood stages. Within the sexual stage in the mosquito, ookinetes develop in the mosquito midgut to form an oocyst which bursts to release sporozoites into the salivary glands [13]. In 2009 the newly founded malaria signaling consortium [14] began to study the molecular mechanisms which enable the parasite to sense and adapt to the intra- and extra-cellular requirements, i.e., invasion of the hepatocytes in the human liver, the erythrocyte stages in the human host and the sexual development in the _Anopheles_ mosquito. In sum, the current results provide evidence that the cyclic nucleotides cAMP or cGMP are essential during stage conversion of the asexual, intraerythrocytic stages to the presexual stages [15]. In particular these cyclic nucleotides are required in exflagellation during male gametogenesis where a gametocyte is converted to a male gamete in the mosquito. However, knowledge about the first part of the pathway, in which a GPCR-mediated signal might be transferred via heterotrimeric G-proteins to adenylyl cyclase is scarce in _Plasmodium_. To understand the pathogenesis of a malaria infection one has to consider both molecular mechanisms of signalingin the human host and the parasite. Signal transduction occurs between the human erythrocyte and the parasitophorous membrane. Studies began in the enucleated human erythrocyte where a set of proteins was identified which were involved in signaling [16]. For an outside-in, signaling in infected erythrocytes membrane receptors such as purinergic receptors were demonstrated to be responsible [17]. Secondly, extracellular ATP increased cation fluxes in human erythrocytes [18] and ion channels were activated during infection with malaria parasites [19]. Thirdly, it was shown [20] that signaling via the erythrocyte-beta-2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (G\(\alpha\)) regulated the entry of the human malaria parasite _Plasmodium falciparum_. Meanwhile there is evidence that cAMP which is not localized to a signal transduction pathway can activate exchange proteins (EPAC) that inhibit ATP release [21]. Collectively, erythrocyte G-proteins reside at the cytoplasmic face of the cellular plasma membrane, where they can couple with a variety of transmembrane receptors to transduce extracellular signals to proteins (G\(\alpha_{s}\)) and thus facilitate invasion of the parasite [22]. Further results revealed that the erythrocyte host G-alpha-s subunit (Gos) which is located at the cytoplasmatic face of the plasma membrane is functional and promotes invasion of the parasite into the erythrocyte [23]. Supplementation of in vitro _P. falciparum_ cultures with propranolol, an antagonist of the G-protein-coupled \(\beta\)-adrenergic receptor inhibited intracellular parasite growth. Thus inhibition of signal transduction via the G\(\alpha\)s in the erythrocyte membrane reduced invasion of the parasite [23]. These results led to the conclusion that signaling in _Plasmodium_ is unlikely to be via heterotrimeric G-proteins from the parasite and depends exclusively on GPCR-mediated signaling in the erythrocyte of the human host. Hitherto, there is no genomic evidence that canonical heterotrimeric G-proteins exist in _Plasmodium_. Apart from the genomic data, biochemical experiments with mastoparan 7 and cholera-toxin (CTX) [24] were performed. CTX stimulates ADP-ribosylation of the Gs alpha-subunit [25] while mastoparan 7 increases GTPase activity. Taken together, from these experiments the authors concluded that only mastoparan 7 significantly increased cAMP levels while cholera toxin induced commitment to gametogenesis without heterotrimeric G-proteins.