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MBC in Press, published online ahead of print November 16, 2005
Mol. Biol. Cell 10.1091/mbc.E05-07-0699

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Submitted on August 1, 2005
Revised on October 28, 2005
Accepted on November 9, 2005

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,{dagger} and Joseph Heitman*{dagger}{ddagger}

Departments of *Molecular Genetics and Microbiology, {dagger}Medicine, and {ddagger}Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710

Monitoring Editor: J. Silvio Gutkind

The G{alpha} 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 S. 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{alpha} 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.

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




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