ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer

doi:10.1016/j.bbrc.2007.12.153

Biochemical and Biophysical Research Communications

Volume 367, Issue 2, 7 March 2008, Pages 440-445

https://doi.org/10.1016/j.bbrc.2007.12.153 Get rights and content

Abstract

The Ca²⁺-modulated ONE-GC membrane guanylate cyclase is a central component of the cyclic GMP signaling in odorant transduction. It is a single transmembrane spanning modular protein. Its intracellular region contains Ca²⁺ sensor recognition domains linked to GCAP1 and to neurocalcin δ, and a catalytic module. These domains sense increments in free Ca²⁺ and stimulate the catalytic module. The present study makes three significant mechanistic advancements. First, to date no ligand for the extracellular (ext) domain is known, for this reason ONE-GC has been deemed as an orphan receptor. The present study identifies its ligand. Uroguanylin stimulates ONE-GC through its ext domain. Second, so far no ligand is known that directly stimulates the catalytic module of any membrane guanylate cyclase. The presented evidence shows that in the presence of the semimicromolar range of free Ca²⁺, neurocalcin binds to the catalytic module and stimulates ONE-GC. Thus, ONE-GC has trimodal regulation, two occurring intracellularly and one extracellularly. Third, guanylin, a urine odorant, does not directly stimulate ONE-GC. This challenges the proposed hypothesis that the guanylin odorant signal occurs via ONE-GC [T. Leinders-Zufall, R.E. Cockerham, S. Michalakis, M. Biel, D.L. Garbers, R.R. Reed, F. Zufall, S.D. Munger, Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium, Proc. Natl. Acad. Sci. USA. 104 (2007) 14507–14512].

Section snippets

Materials and methods

Materials. Uroguanylin (human) and guanylin (rat) were purchased from Bachem, myristoylated neurocalcin δ was expressed and purified according to the laboratory protocol [18].

ONE-GC mutants. The ONE-GC mutants used in this study with their domain structures are schematically represented in Fig. 1. The transmembrane-bound tm-catd mutant (deleted aa regions 75–466, 521–879, and 1029–1110) was prepared by introducing TGA STOP codon into the ONE-GC Δ75–466 & 521–823 mutant [13] and by introducing

The peptide uroguanylin but not guanylin stimulates ONE-GC

Original cloning of ONE-GC from total rat olfactory cDNA library showed that it was a membrane guanylate cyclase [11]. Because it had no known extracellular ligand, it was named an orphan receptor guanylate cyclase [11]. To date this picture has not changed and the guanylate cyclase remains an orphan receptor.

A recent patch clamp study has indicated that ONE-GC is the signal transducer of two urine odorant constituents, uroguanylin and guanylin [14]. The signal transduction mechanisms of these

Acknowledgments

The study was supported by NIH awards DC 005349 (R.K.S.) and HL 070015 (T.D.).

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Citation Excerpt :
Therefore, the observed biological effects of Cys-ANF(4-18) might be due to a combined effect related to clearance receptor binding and direct ANP receptor stimulation. Recently, different ligands have been proposed as GC-D agonists, namely guanylin and uroguanylin (Leinders-Zufall et al., 2007), uroguanylin but not guanylin (Duda and Sharma, 2008) and bicarbonate ions (Hu et al., 2007; Sun et al., 2009). Up to now, the proposed GC-D ligands are controversely discussed and should be confirmed independently.
Receptor guanylyl cyclases are implicated in a growing number of pathophysiologies and, therefore, represent an important target class for drug development. We report here the generation and pharmacological characterization of three particulate guanylyl cyclase (pGC) reporter cell lines. Plasmid constructs encoding the natriuretic peptide receptors GC-A and GC-B, and the heat-stable enterotoxin receptor GC-C, were stably transfected in a parental reporter cell line expressing a cyclic nucleotide-gated (CNG) cation channel, acting as the biosensor for intracellular cGMP. In our reporter cell lines pGC activity can be monitored in living cells in real-time . By using different natural as well as synthetic receptor ligands of the natriuretic and guanylin peptide families, we show that our reporter assay monitors pGC activity with very high sensitivity. In contrast to previous findings, we could detect significant stimulation of GC-A and GC-B by each of the natriuretic peptides ANP, BNP and CNP. In addition, the clearance receptor ligand Cys-ANF(4–18) and the ANP receptor antagonist Arg-ANF(6–18) were characterized as partial GC-A agonists. The results imply that our novel pGC reporter cell lines are well suited for the characterization of receptor pharmacology and may be used for natural ligand characterization of guanylyl cyclase orphan receptors.

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ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer

Abstract

Section snippets

Materials and methods

The peptide uroguanylin but not guanylin stimulates ONE-GC

Acknowledgments

Comp. Biochem. Physiol. A Mol. Integr. Physiol.

Curr. Opin. Neurobiol.

Neuron

Cell

Cell

Arch. Biochem. Biophys.

The cellular and molecular basis of odor adaptation

Chem. Senses

Transduction mechanisms in vertebrate olfactory receptor cells

Physiol. Rev.

Constitution and operational principles of the retinal and odorant-linked neurocalcin δ-dependent Ca2+ modulated ROS-GC transduction machinery

Olfactory receptors: molecular basis for recognition and discrimination of odors

Anal. Bioanal. Chem.

Structural activation pathways from dynamic olfactory receptor-odorant interactions

Chem. Senses

Constitution and operational principles of the retinal and odorant-linked neurocalcin δ-dependent Ca²⁺ modulated ROS-GC transduction machinery