cAMP Signalling in the Kinetoplastid Protozoa

Abstract

Several species of kinetoplastid protozoa cause major human infectious diseases. Trypanosoma cruzi is responsible for the fatal Chagas disease in large parts of South America, the various species of Leishmania cause a number of different human diseases with millions of patients world-wide, and the African trypanosome Trypanosoma brucei is the agent of human sleeping sickness, a disastrously re-emerging epidemic of fatal infections in Sub-Saharan Africa. Chemotherapy of all of these infections is in a very unsatisfactory state. cAMP signalling pathways in humans have provided interesting drug targets for a number of clinical conditions, from asthma to impotency. Similarly, cAMP signalling in kinetoplastids might offer useful targets for the development of novel antiparasitic drugs, which makes their exploration an urgent need. Current knowledge suggests that cAMP signalling proceeds along very similar pathways in all kinetoplastid pathogens (T. cruzi, the Leishmanias and T. brucei). Their adenylyl cyclases are structurally very different from the human enzymes and appear to function as enzyme-linked cell surface receptors. They might represent the major sensory apparatus of the kinetoplastids, guiding much of their environmental sensing and host/parasite interaction. The cAMP-specific phosphodiesterases of the kinetoplastids are rather similar to those of human cells and might function in similar ways. Essentially nothing is known on downstream effectors of cAMP in the kinetoplastids. Homologues of protein kinase A and its regulatory subunits have been identified, but their biochemical properties seem to be disctinct from that of mammalian protein kinase A.

Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi , the Etiological Agent of Chagas' Disease

“…Unfortunately, this different sensitivity of trypanosomatid PDEs to mammalian PDE inhibitors was overlooked in many experiments where inhibitors of mammalian PDEs were used uncritically for studying cyclic AMP effects in different trypanosomatids (30). Although many of these inhibitors did have an effect on trypanosomes, the effects observed may not be due entirely to cyclic AMP (30).…”

“…Unfortunately, this different sensitivity of trypanosomatid PDEs to mammalian PDE inhibitors was overlooked in many experiments where inhibitors of mammalian PDEs were used uncritically for studying cyclic AMP effects in different trypanosomatids (30). Although many of these inhibitors did have an effect on trypanosomes, the effects observed may not be due entirely to cyclic AMP (30). Our identification of a number of TcrPDEC inhibitors that were shown to increase cyclic AMP in intact parasites and stimulate their regulatory volume decrease will greatly facilitate the understanding of the role of this nucleotide in osmoregulation, as well as in proliferation and differentiation.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…ACs from parasites such as Trypanosoma brucei are also drug targets (Seebeck et al, 2004;Makin and Gluenz, 2015). 94 Dessauer et al AC and cAMP were first described by Nobel laureate Earl W. Sutherland (Rall and Sutherland, 1958;Sutherland et al, 1962).…”

Kinetoplastid AGC Kinases

“…The presence of cAMP and enzymes of cAMP metabolism in trypanosomatids is well documented [31,36,37], and a functional role of this second messenger for essential intracellular processes has been demonstrated both genetically and, more recently, pharmacologically [38][39][40]. Not surprisingly, genes encoding orthologs of PKA subunits have been found in several trypanosomatids [35,[41][42][43][44][45][46][47].…”

“…Changes in intracellular cAMP levels during the differentiation of T. brucei [55], T. cruzi [56] or L. donovani [57] have suggested cAMP signaling and, by inference, kinetoplastid PKA as regulators of life cycle stage differentiation of the three kinetoplastids [31,36,37]. In T. cruzi, cAMP levels are higher in trypomastigotes compared to epimastigotes [56].…”