Reports

Erythrocyte G Protein-Coupled Receptor Signaling in Malarial Infection

Travis Harrison,^1,2 Benjamin U. Samuel,^1,2* Thomas Akompong,^1,2 Heidi Hamm,³ Narla Mohandas,⁴ Jon W. Lomasney,¹ Kasturi Haldar^1,2

Erythrocytic mechanisms involved in malarial infection are poorly understood. We have found that signaling via the erythrocyte ß2-adrenergic receptor and heterotrimeric guanine nucleotide–binding protein (Gs) regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cyclic adenosine 3',5'-monophosphate production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit Gs protein function reduced parasitemia in P. falciparum cultures in vitro, and ß-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Thus, signaling via the erythrocyte ß2-adrenergic receptor and Gs may regulate malarial infection across parasite species.

¹ Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 Chicago Avenue, Chicago, IL 60611, USA.
² Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 Chicago Avenue, Chicago, IL 60611, USA.
³ Department of Pharmacology, Vanderbilt University, Nashville, TN 37240, USA.
⁴ New York Blood Center, New York, NY 10021, USA.

^* Present address: Department of Ophthalmology and Visual Sciences, University of Chicago, Room 103 Visual Science Center, Chicago, IL 60637, USA.

To whom correspondence should be addressed. E-mail: k-haldar{at}northwestern.edu (K.H.); j-lomasney{at}northwestern.edu (J.W.L.)

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Cytoplasmic remodeling of erythrocyte raft lipids during infection by the human malaria parasite Plasmodium falciparum.

S. C. Murphy, S. Fernandez-Pol, P. H. Chung, S. N. Prasanna Murthy, S. B. Milne, M. Salomao, H. A. Brown, J. W. Lomasney, N. Mohandas, and K. Haldar (2007)
Blood 110, 2132-2139
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PfPKB, a Protein Kinase B-like Enzyme from Plasmodium falciparum: II. IDENTIFICATION OF CALCIUM/CALMODULIN AS ITS UPSTREAM ACTIVATOR AND DISSECTION OF A NOVEL SIGNALING PATHWAY.

A. Vaid and P. Sharma (2006)
J. Biol. Chem. 281, 27126-27133
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Delivery of the Malaria Virulence Protein PfEMP1 to the Erythrocyte Surface Requires Cholesterol-Rich Domains.

S. Frankland, A. Adisa, P. Horrocks, T. F. Taraschi, T. Schneider, S. R. Elliott, S. J. Rogerson, E. Knuepfer, A. F. Cowman, C. I. Newbold, et al. (2006)
Eukaryot. Cell 5, 849-860
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Fas-, Caspase 8-, and Caspase 3-dependent Signaling Regulates the Activity of the Aminophospholipid Translocase and Phosphatidylserine Externalization in Human Erythrocytes.

D. Mandal, A. Mazumder, P. Das, M. Kundu, and J. Basu (2005)
J. Biol. Chem. 280, 39460-39467
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Intracellular Parasite Invasion Strategies.

L. D. Sibley (2004)
Science 304, 248-253
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Erythrocyte detergent-resistant membrane proteins: their characterization and selective uptake during malarial infection.

S. C. Murphy, B. U. Samuel, T. Harrison, K. D. Speicher, D. W. Speicher, M. E. Reid, R. Prohaska, P. S. Low, M. J. Tanner, N. Mohandas, et al. (2004)
Blood 103, 1920-1928
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