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

Tagoe, D. N. A., Kalejaiye, T. D. and De Koning, H. P. (2015) The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference! Frontiers in Pharmacology, 6, 185. (doi:10.3389/fphar.2015.00185) (PMID:26441645) (PMCID:PMC4561360)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kalejaiye, Miss Titilola and De Koning, Professor Harry
Authors: Tagoe, D. N. A., Kalejaiye, T. D., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Pharmacology
Publisher:Frontiers
ISSN:1663-9812
ISSN (Online):1663-9812
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Frontiers in Pharmacology 6:185
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
590521Wellcome 096984/Z - D TagoeHarry De KoningWellcome Trust (WELLCOME)096984/Z/11/ZIII - PARASITOLOGY
590522Wellcome 096984/Z - D TagoeHarry De KoningWellcome Trust (WELLCOME)096984/Z/11/ZIII - PARASITOLOGY
371796The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)085349/Z/08/ZIII - PARASITOLOGY
371798The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)085349/B/08/ZIII - PARASITOLOGY
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY