Two different avian cold-sensitive sensory neurons: Transient receptor potential melastatin 8 (TRPM8)-dependent and -independent activation mechanisms
Introduction
Temperature is a critical environmental factor in homeostasis and sensing it is one of the important functions for survival and adaptation to the environment in animals (Young et al., 1989). For example, noxious heat and cold are highly unfavorable sensations that trigger powerful escape reactions in most animals. These thermosensations are involved in the regulation of physiological body temperature in mammals (Bandell et al., 2007). Mammals sense the ambient temperature through primary afferent sensory neurons of the dorsal root ganglia (DRG) or trigeminal ganglia (TG), primarily small diameter neurons. In a variety of animal species, the sensing of the ambient temperature is performed through various mechanisms (Saito and Tominaga, 2015), including a subset of temperature-sensitive transient receptor potential (TRP) channels that are called “thermoTRP” channels (Patapoutian et al., 2003). Comparison of the functions of thermoTRP channels among various species may also help to elucidate how specific channels are activated by temperature changes.
Most thermoTRP channels are calcium-permeable nonselective cation channels and are not only activated by thermal stimuli but also by other physical and chemical stimuli (Laing and Dhaka, 2016). Their activation leads to an influx of Ca2+ and Na+ into the cells and triggers downstream signal transduction (Bourinet et al., 2014). ThermoTRP channels have been characterized in a variety of animal species and are functionally diverse among species. For example, TRPV3 is known to be activated by warm temperatures in mammals (Xu et al., 2002), whereas it is activated by cold temperatures in amphibians (Saito et al., 2011). TRPA1 has been determined to be a putative sensor for noxious cold in mice (Story et al., 2003, Bandell et al., 2004). However, the temperature sensitivity of TRPA1 in mammals is a matter of debate. For example, primate TRPA1 is non-temperature sensitive, but rodent TRPA1 is cold sensitive (Chen et al., 2013). On the other hand, human TRPA1 expressed in artificial membranes is intrinsically cold sensitive (Moparthi et al., 2014). TRPA1 has been estimated as not only a cold sensor but also a heat sensor along with laws of thermodynamics (Clapham and Miller, 2011). A recent report using purified human TRPA1 inserted into lipid bilayer show that human TRPA1 is heat-sensitive (Moparthi et al., 2016). Amphibian and reptile TRPA1s are heat sensitive (Saito et al., 2012). Thus these species differences may be due to the difference in the thermoregulatory mechanisms of body temperature between homeotherms and poikilotherms. Recently, we characterized chicken TRPA1 (cTRPA1) and found that the channel functions as a heat sensor (Saito et al., 2014), and possesses unique chemical sensitivity compared to mammalian TRPA1 (Banzawa et al., 2014).
TRPM8 has been proposed to detect cold temperatures in the innocuous and noxious ranges of temperature (McKemy et al., 2002, Peier et al., 2002). This channel is also activated by cooling mimetic compounds such as menthol and the super-cooling agent icilin (McKemy, 2007). It has been reported that TRPM8 is mainly expressed in peripheral sensory pathways in mammals (McKemy et al., 2002, Story et al., 2003, Bautista et al., 2007). However, the functional role and pharmacological properties of chicken TRPM8 (cTRPM8) have not been fully understood. In addition, the cellular and molecular mechanisms of cold sensing in avian species are not well understood. As noted above, TRPA1, which potentially acts as a cold-sensor in mammals, is sensitive to heat in avian species, suggesting physiological roles of orthologues channels might differ among species (Saito et al., 2014). Therefore, investigation of cold sensing neurons of chicken may reveal novel molecular mechanisms which have not been recognized yet.
In the present study, therefore, we investigated the thermal sensitivity and pharmacological properties, using several agonists and antagonists that are effective on mammalian TRPM8, on heterologously and endogenously expressing cTRPM8. We also characterize the cold-sensing mechanisms in chicken DRG (cDRG) neurons. To analyze the channel activity, we used fura-2-based [Ca2+]i-imaging techniques with a series of pharmacological interventions since most TRP channels are highly Ca2+ permeable (Bourinet et al., 2014).
The present results indicate that menthol and its related compound WS-12 excite chicken sensory neurons via the activation of cTRPM8. While, icilin selectively activated cTRPA1. Similar to mammals' orthologues, cTRPM8 functions as a cold-sensitive channel. In addition, we found the presence of a cold-sensing mechanism that is independent of TRPM8 in chicken. Interestingly, in cDRG neurons, menthol-insensitive cold-sensitive neurons were abundant and these [Ca2+]i responses were mediated via Ca2+ release from intracellular stores in a manner distinct from mammals. We suggest that these mechanisms are specific for temperature regulation in avian species.
Section snippets
Isolation of dorsal root ganglion neurons
All procedures involved in the care and use of animals were approved by the committee on Animal Experimentation of Tottori University. All efforts were made to minimize the number of animals used. Fertilized chicken eggs were incubated (37 °C) until they reached the desired stages (embryonic day 17 to postnatal day 1; ED 17-PD 1). Adult chickens were obtained from a poultry farm in Tottori, Japan. DRG neurons were obtained from chicken according to the procedure reported previously (Banzawa
Sensitivities to mammalian TRPM8 agonists on cTRPM8
We first examined the sensitivities of cTRPM8 to mammalian TRPM8 agonists, menthol, WS-12 and icilin. Fig. 1A shows typical [Ca2+]i responses to these agonists in HEK293 cells expressing cTRPM8. Menthol increased [Ca2+]i in a concentration-dependent manner with a half maximal effective concentration (EC50) of 8.4 ± 1.1 μM (Fig. 1B). The menthol sensitivity of cTRPM8 was higher than that of mTRPM8 (22.6 ± 1.7 μM, Fig. 1C). Chicken TRPM8 was also activated by another TRPM8 agonist, WS-12, with a
Discussion
We characterized the functional properties of cTRPM8 in heterologously expressed cells and cultured sensory neurons. We clarified that cTRPM8 was activated by several cooling compounds as well as cold stimulation like its mammalian orthologue. We also showed that icilin selectively activated TRPA1 instead of TRPM8 in the chicken. In chicken sensory neurons, it was found that there were two cold-sensing mechanisms, one was TRPM8-dependent and the other TRPM8-independent. The latter was mediated
Conflict of interest
We have no conflict-of-interest to declare.
Acknowledgments
This work was supported, in whole or part, by a JSPS KAKENHI (Grant Number 26292150), Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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