QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 2, 667-679, February 2006

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E05-07-0699v1 17/2/667    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xue, C. Articles by Heitman, J. Search for Related Content PubMed PubMed Citation Articles by Xue, C. Articles by Heitman, J.

G Protein-coupled Receptor Gpr4 Senses Amino Acids and Activates the cAMP-PKA Pathway in Cryptococcus neoformans

Chaoyang Xue ^*, Yong-Sun Bahn ^*, Gary M. Cox , and Joseph Heitman ^*  

^* Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; Department of Medicine, Duke University Medical Center, Durham, NC 27710; and Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710

Submitted August 1, 2005; Revised October 28, 2005; Accepted November 9, 2005
Monitoring Editor: J. Silvio Gutkind

The G protein Gpa1 governs the cAMP-PKA signaling pathway and plays a central role in virulence and differentiation in the human fungal pathogen Cryptococcus neoformans, but the signals and receptors that trigger this pathway were unknown. We identified seven putative proteins that share identity with known G protein-coupled receptors (GPCRs). One protein, Gpr4, shares limited sequence identity with the Dictyostelium discoideum cAMP receptor cAR1 and the Aspergillus nidulans GPCR protein GprH and also shares structural similarity with the Saccharomyces cerevisiae receptor Gpr1. gpr4 mutants exhibited reduced capsule production and mating defects, similar to gpa1 mutants, and exogenous cAMP suppressed both gpr4 mutant phenotypes. Epistasis analysis provides further evidence that Gpr4 functions upstream of the G subunit Gpa1. Gpr4-Gpr4 homomeric interactions were observed in the yeast two-hybrid assay, and Gpr4 was shown to physically interact with Gpa1 in the split-ubiquitin system. A Gpr4::DsRED fusion protein was localized to the plasma membrane and methionine was found to trigger receptor internalization. The analysis of intracellular cAMP levels showed that gpr4 mutants still respond to glucose but not to certain amino acids, such as methionine. Amino acids might serve as ligands for Gpr4 and could contribute to engage the cAMP-PKA pathway. Activation of the cAMP-PKA pathway by glucose and amino acids represents a nutrient coincidence detection system shared in other pathogenic fungi.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Joseph Heitman (heitm001{at}duke.edu).

This article has been cited by other articles:

				G. Shen, Y.-L. Wang, A. Whittington, L. Li, and P. Wang The RGS Protein Crg2 Regulates Pheromone and Cyclic AMP Signaling in Cryptococcus neoformans Eukaryot. Cell, September 1, 2008; 7(9): 1540 - 1548. [Abstract] [Full Text] [PDF]

				A. Yoneda and T. L. Doering Regulation of Cryptococcus neoformans Capsule Size Is Mediated at the Polymer Level Eukaryot. Cell, March 1, 2008; 7(3): 546 - 549. [Abstract] [Full Text] [PDF]

				L. Li, G. Shen, Z.-G. Zhang, Y.-L. Wang, J. K. Thompson, and P. Wang Canonical Heterotrimeric G Proteins Regulating Mating and Virulence of Cryptococcus neoformans Mol. Biol. Cell, November 1, 2007; 18(11): 4201 - 4209. [Abstract] [Full Text] [PDF]

				X. Zhao, R. Mehrabi, and J.-R. Xu Mitogen-Activated Protein Kinase Pathways and Fungal Pathogenesis Eukaryot. Cell, October 1, 2007; 6(10): 1701 - 1714. [Full Text] [PDF]

				Y.-P. Hsueh, C. Xue, and J. Heitman G protein signaling governing cell fate decisions involves opposing G{alpha} subunits in Cryptococcus neoformans Mol. Biol. Cell, September 1, 2007; 18(9): 3237 - 3249. [Abstract] [Full Text] [PDF]

				S. Biswas, P. Van Dijck, and A. Datta Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans Microbiol. Mol. Biol. Rev., June 1, 2007; 71(2): 348 - 376. [Abstract] [Full Text] [PDF]

				A. Idnurm, S. S. Giles, J. R. Perfect, and J. Heitman Peroxisome Function Regulates Growth on Glucose in the Basidiomycete Fungus Cryptococcus neoformans Eukaryot. Cell, January 1, 2007; 6(1): 60 - 72. [Abstract] [Full Text] [PDF]

				D. A. Palmer, J. K. Thompson, L. Li, A. Prat, and P. Wang Gib2, A Novel Gbeta-like/RACK1 Homolog, Functions as a Gbeta Subunit in cAMP Signaling and Is Essential in Cryptococcus neoformans J. Biol. Chem., October 27, 2006; 281(43): 32596 - 32605. [Abstract] [Full Text] [PDF]

				S.-K. Kim, K. E. Bissati, and C. B. Mamoun Amino acids mediate colony and cell differentiation in the fungal pathogen Candida parapsilosis. Microbiology, October 1, 2006; 152(Pt 10): 2885 - 2894. [Abstract] [Full Text] [PDF]

				S. Krystofova and K. A. Borkovich The Predicted G-Protein-Coupled Receptor GPR-1 Is Required for Female Sexual Development in the Multicellular Fungus Neurospora crassa. Eukaryot. Cell, September 1, 2006; 5(9): 1503 - 1516. [Abstract] [Full Text] [PDF]

				L. Li and K. A. Borkovich GPR-4 Is a Predicted G-Protein-Coupled Receptor Required for Carbon Source-Dependent Asexual Growth and Development in Neurospora crassa. Eukaryot. Cell, August 1, 2006; 5(8): 1287 - 1300. [Abstract] [Full Text] [PDF]