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The predator odor 2,4,5-trimethylthiazoline binds and activates receptor guanylyl cyclase-G to elicit innate defensive responses


Guanylyl cyclase (GC)-G is the last member of the receptor GC family [1, 2]. Our recent studies demonstrated that GC-G expressed in Grueneberg Ganglion (GG) neurons can be activated by cool temperatures to generate ultrasound calls by isolated pups to elicit maternal care [3]. Detecting the semiochemical warnings present in the environment is essential for species survival. The mouse GG is the olfactory subsystem that also detects alarm pheromones (APs) and other structurally-related chemicals involuntary released by rodent's predators [4, 5]. The predator odor 2,4,5-trimethylthiazoline (TMT), a volatile compound originally isolated from the anal secretions of the red fox, induces robust freezing behaviors in mice. TMT shared a similar chemical structure to APs and can activate GG neurons [5]. However, whether TMT can directly bind and stimulate GC-G activity to trigger innate fear responses remains unknown.

Materials and methods

A combination of biochemical and molecular biology methods, Ca2+ imaging as well as behavioural studies comparing wild-type and GC-G-knockout (KO) mice was used to elucidate the molecular and biological function of GC-G in transmitting TMT signaling.


We show that GC-G can be stimulated by TMT in both in vivo cellular cGMP accumulation assays and in vitro GC assays with isolated GC-G membranes protein. Furthermore, domain deletion analysis verifies that the extracellular domain of GC-G is required for TMT-induced cGMP production. A direct interaction with notable affinity between TMT and GC-G extracellular domain was confirmed by time-resolved surface plasmon resonance. HEK-293T cells co-expressing GC-G and the cGMP-activated ion channel CNGA3 respond to TMT via a rapid influx of calcium. In line with these findings, TMT-induced calcium transients in the GG as well as TMT-evoked innate fear behaviors and an increase of serum corticosterone (a stress hormone) were markedly attenuated in the GC-G-KO mice compared to wild-type littermates.


Our data demonstrated for the first time that TMT may be a potential ligand for GC-G receptor and unravelled the molecular interaction involved in the inter-specific olfactory message communication between predators and preys via TMT-GC-G signaling.


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Correspondence to Ying-Chi Chao.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Chao, YC., Yang, RB. The predator odor 2,4,5-trimethylthiazoline binds and activates receptor guanylyl cyclase-G to elicit innate defensive responses. BMC Pharmacol Toxicol 16 (Suppl 1), A40 (2015).

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