The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

Daniel N A Tagoe,Titilola D Kalejaiye,Harry P De Koning

doi:10.3389/fphar.2015.00185

Abstract

Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics.

Highlights

Trypanosomatids are protozoan parasites belonging to the order kinetoplastida, family trypanosomatidae, and are characterized by a particular substructure of the mitochondrion, called the kinetoplast, which contains the mitochondrial DNA
It has been estimated that the core group of neglected tropical diseases (NTDs), the majority of which are caused by trypanosomatids, results in the loss of more than 57 million disability-adjusted life years (DALY), coupled with attendant impacts on poverty (Hotez et al, 2006, 2009)
In bloodstream forms (BSFs) of T. brucei, the most unambiguous role of cAMP is in cytokinesis, as either the knockdown of adenylyl cyclases (ACs) (Salmon et al, 2012a), knockdown of TbrPDEB1 and B2 (Oberholzer et al, 2007) or the pharmacological inhibition of these PDEs all lead to severe defects in the cytokinesis phase of cell division, resulting in misshaped cells with multiple nuclei and kinetoplasts, that are non-viable

Summary

Introduction

Trypanosomatids are protozoan parasites belonging to the order kinetoplastida, family trypanosomatidae, and are characterized by a particular substructure of the mitochondrion, called the kinetoplast, which contains the mitochondrial DNA. They are digenetic flagellated protozoans with similar cellular structures as well as similar genome organization and are all known to undergo morphological transformations during their life cycles (Stuart et al, 2008). CAMP signaling in trypanosomatids unicellular eukaryotes, and many of them parasitize multicellular organisms and cause medically and economically important diseases in humans, their domestic animals and cash crops (Barrett et al, 2003). Downstream effectors of cAMP are very different in human and trypanosomatid cells, potentially providing further drug targets, this time without mammalian counterparts

Signal Transduction in Trypanosomatids

Novel Downstream Effectors of cAMP in Trypanosomes

Summary and Outlook