This Research Topic is aimed towards collecting the present knowledge of structure and function of sensory receptors in the animal kingdom, as well as the mechanisms of signal transduction and downstream signal amplification. The term sensory receptor applies for sensory modalities reflecting the outer world (vision, audition, olfaction etc.), the inner world (pH, osmolarity, glucose level etc.) or both such as temperature and pain.

Max Planck Institute for Chemical Ecology

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Frontiers in Cellular Neuroscience

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Non-Neuronal Cells

Cellular Neurophysiology

Cellular Neuropathology

Design principles of sensory receptors

This research topic was aimed toward collecting the present knowledge of structure and function of sensory receptors in animal kingdom as well as the mechanisms of signal transduction and amplification. To translate external signals such as light, sound, smell, etc., into an appropriate intracellular signal, sensory receptors use either a fast, direct or a slow, indirect way. These qualitatively different signal transduction pathways are now usually called ionotopic or metabotropic. Historically, the term metabotropic receptor has been introduced to distinguish a subtype of glutamate receptors that triggers chemical reactions (cell metabolism) in the postsynaptic cell from other glutamate receptors that pass an ion current (ionotropic) (<a href="#B3">Eccles and McGeer, 1979</a>). Metabotropic glutamate receptors were found to be linked to inositol phospholipid metabolism (<a href="#B15">Sugiyama et al., 1987</a>), and were subsequently identified as G-protein-coupled receptors (GPCRs) (<a href="#B7">Masu et al., 1991</a>). The terminology ionotropic/metabotropic has been extended to other neurotransmitter receptors, such as for nicotinic/muscarinergic acetyl choline or GABAA/GABAB receptors. All metabotropic neurotransmitter receptors are GPCRs. There are, however, a large number of non-GPCRs that also fulfill the original definition for a metabotropic receptor, namely “that the transmitter acts indirectly, by triggering a chemical reaction or a series of reactions” (<a href="#B3">Eccles and McGeer, 1979</a>). Accordingly, it has been used to extent the term metabotropic receptor to receptor kinases, receptor cyclases, etc., as well.Sensory receptors are often part of complex signal transduction cascades. An ion current through an ionotropic receptor may initiate metabotropic signaling, as well as a metabotropic receptor may downstream affect the function of ion channels. An example for protein–protein interaction in chemosensation is given in the original article by <a href="#B6">Liu et al. (2012)</a>. The authors identified so far unknown binding partners of Gγ13, a G-protein subunit expressed in mammalian taste and olfactory receptor cells. These binding partners are PDZ-domain containing proteins assumed to target Gγ13 to specific subcellular locations or represent parts of the chemosensory signal transduction cascade.The evolution of chemoreceptors shows that—from bacteria to mammals—both, ionotropic as well as metabotropic mechanisms were conserved. Functional aspects of chemoreceptors, including the interaction of electrical and chemical signaling, and the amplification of sensory information are discussed in the perspective article (<a href="#B16">Wicher, 2012</a>). Intriguingly, insect chemoreceptors operate as ionotropic receptors, namely odorant receptors (ORs), ionotropic glutamate-like receptors (IRs), and gustatory receptors (GRs). <a href="#B4">Getahun et al. (2012)</a> investigate the temporal response dynamics of insect chemoreceptors and demonstrate that olfactory sensory neurons (OSNs) expressing ORs, GRs, or IRs differ in their response kinetics to brief stimuli. OR-expressing neurons respond faster and with higher sensitivity, while IR-expressing neurons do not adapt to long stimulations. Although ORs primarily operate as ionotropic receptors, metabotropic signaling was seen to modulate the ionotropic odor response (<a href="#B11">Olsson et al., 2011</a>; <a href="#B14">Sargsyan et al., 2011</a>). Stimulation of cAMP production enhanced the response to a given odor concentration, corresponding to an increased sensitivity. This type of modulation may constitute the mechanistic basis for the higher sensitivity of ORs compared with IRs.Chemical information released from different sources may interfere during processing in the nervous system and affect the response of an organism. Odor mixtures can act in synergistic or in an inhibitory way. On the level of the chemoreceptors the existence of a huge number of different chemical signal molecules leads to the intriguing question of receptor specificity and whether a given chemical signal is perceived independent of the background. The interaction of odorant and pheromone detection in moths is reported by <a href="#B13">Pregitzer et al. (2012)</a> and commented by <a href="#B1">Anton and Renou (2012)</a>. Certain plant odors are known to inhibit the activation of pheromone receptors. The reported investigations provide evidence that the odorant-pheromone interaction already takes place at the receptor level.Since the first editorial to this topic was written in 2010 recent progress shed new light on structure and function of certain receptors. Channelrhodopsins, for example, are photoreceptors in green algae which conduct a current upon illumination. They are seven transmembrane (7-TM)-spanning proteins as typical for GPCRs but do not couple to a heterotrimeric G-protein. With the given 7-TM topology it was as yet not clear how the channelrhodopsin proteins have to arrange to form an ion channel. Recently, the non-selective cation channel, channelrhodopsin-2 from Chlamydomonas reinhardtii has been successfully crystallized (<a href="#B8">Müller et al., 2011</a>; <a href="#B5">Kato et al., 2012</a>). The channelrhodopsin-2 proteins were found to stably dimerize in such an arrangement that the third and the fourth TM helix of each protein align to a tetramer thereby lining the cation-permeable pore. Another example for ion channel-forming 7-TM proteins are the above mentioned insect ORs. In contrast to homodimeric channelrhodopsin channels they are heterodimers, composed of variable, odorant-binding protein OrX, and an ubiquitous co-receptor OrCo. There is growing evidence that both OR proteins contribute to channel pore formation and determine their properties such as the ion permeability and pharmacological properties (<a href="#B10">Nichols et al., 2011</a>; <a href="#B12">Pask et al., 2011</a>; <a href="#B9">Nakagawa et al., 2012</a>). It remains to be established whether OrCo form homomeric channels in the receptor neurons as seen in the heterologous expression system and whether they represent the metabotropic pathway used to tune the sensitivity of the ionotropic receptor (<a href="#B11">Olsson et al., 2011</a>; <a href="#B14">Sargsyan et al., 2011</a>). The role of stimulatory G-proteins in olfactory signaling has been demonstrated (<a href="#B2">Deng et al., 2011</a>), and also downstream signaling such as cAMP production were seen to affect the odor response of receptor neurons (<a href="#B11">Olsson et al., 2011</a>). These recent findings on insect OR function modify the view to classify them. While in the first editorial they have been considered as combined metabotropic and ionotropic receptors, they might now be more appropriately characterized as metabotropically regulated ionotropic receptors. This change of view illustrates the highly dynamic development in the field.

Sensory receptors—design principles revisited

Insect olfactory sensory neurons (OSN) express a diverse array of receptors from different protein families, i.e. ionotropic receptors (IR), gustatory receptors (GR) and odorant receptors (OR). It is well known that insects are exposed to a plethora of odor molecules that vary widely in both space and time under turbulent natural conditions. In addition to divergent ligand specificities, these different receptors might also provide an increased range of temporal dynamics and sensitivities for the olfactory system. To test this, we challenged different Drosophila OSNs with both varying stimulus durations (10–2000 ms), and repeated stimulus pulses of key ligands at various frequencies (1–10 Hz). Our results show that OR-expressing OSNs responded faster and with higher sensitivity to short stimulations as compared to IR- and Gr21a-expressing OSNs. In addition, OR-expressing OSNs could respond to repeated stimulations of excitatory ligands up to 5 Hz, while IR-expressing OSNs required ~5x longer stimulations and/or higher concentrations to respond to similar stimulus durations and frequencies. Nevertheless, IR-expressing OSNs did not exhibit adaptation to longer stimulations, unlike OR- and Gr21a-OSNs. Both OR- and IR-expressing OSNs were also unable to resolve repeated pulses of inhibitory ligands as fast as excitatory ligands. These differences were independent of the peri-receptor environment in which the receptors were expressed and suggest that the receptor expressed by a given OSN affects both its sensitivity and its response to transient, intermittent chemical stimuli. OR-expressing OSNs are better at resolving low dose, intermittent stimuli, while IR-expressing OSNs respond more accurately to long-lasting odor pulses. This diversity increases the capacity of the insect olfactory system to respond to the diverse spatiotemporal signals in the natural environment.

Insect olfactory sensory neurons (OSN) express a diverse array of receptors from different protein families, i.e. ionotropic receptors (IR), gustatory receptors (GR) and odorant receptors (OR). It is well known that insects are exposed to a plethora of odor molecules that vary widely in both space and time under turbulent natural conditions. In addition to divergent ligand specificities, these different receptors might also provide an increased range of temporal dynamics and sensitivities for the olfactory system. To test this, we challenged different Drosophila OSNs with both varying stimulus durations (10–2000 ms), and repeated stimulus pulses of key ligands at various frequencies (1–10 Hz). Our results show that OR-expressing OSNs responded faster and with higher sensitivity to short stimulations as compared to IR- and Gr21a-expressing OSNs. In addition, OR-expressing OSNs could respond to repeated stimulations of excitatory ligands up to 5 Hz, while IR-expressing OSNs required ~5x longer stimulations and/or higher concentrations to respond to similar stimulus durations and frequencies. Nevertheless, IR-expressing OSNs did not exhibit adaptation to longer stimulations, unlike OR- and Gr21a-OSNs. Both OR- and IR-expressing OSNs were also unable to resolve repeated pulses of inhibitory ligands as fast as excitatory ligands. These differences were independent of the peri-receptor environment in which the receptors were expressed and suggest that the receptor expressed by a given OSN affects both its sensitivity and its response to transient, intermittent chemical stimuli. OR-expressing OSNs are better at resolving low dose, intermittent stimuli, while IR-expressing OSNs respond more accurately to long-lasting odor pulses. This diversity increases the capacity of the insect olfactory system to respond to the diverse spatiotemporal signals in the natural environment.

Temporal response dynamics of Drosophila olfactory sensory neurons depends on receptor type and response polarity

The perception and processing of chemical signals from the environment is essential for any living systems and is most probably the first sense developed in life. This perspective discusses the physical limits of chemoreception and gives an overview on the receptor types developed during evolution to detect chemical signals from the outside world of an organism. It discusses the interaction of chemoreceptors with downstream signaling elements, especially the interaction between electrical and chemical signaling. It is further considered how the primary chemosignal is appropriately amplified. Three examples of chemosensory systems illustrate different strategies of such amplification.

The perception and processing of chemical signals from the environment is essential for any living systems and is most probably the first sense developed in life. This perspective discusses the physical limits of chemoreception and gives an overview on the receptor types developed during evolution to detect chemical signals from the outside world of an organism. It discusses the interaction of chemoreceptors with downstream signaling elements, especially the interaction between electrical and chemical signaling. It is further considered how the primary chemosignal is appropriately amplified. Three examples of chemosensory systems illustrate different strategies of such amplification.

Functional and evolutionary aspects of chemoreceptors

A first glance on the molecular mechanisms of pheromone-plant odor interactions in moth antennae

In many insects, mate finding relies on female-released sex pheromones, which have to be deciphered by the male olfactory system within an odorous background of plant volatiles present in the environment of a calling female. With respect to pheromone-mediated mate localization, plant odorants may be neutral, favorable, or disturbing. Here we examined the impact of plant odorants on detection and coding of the major sex pheromone component, (Z)-11-hexadecenal (Z11-16:Ald) in the noctuid moth Heliothis virescens. By in vivo imaging the activity in the male antennal lobe (AL), we monitored the interference at the level of olfactory sensory neurons (OSN) to illuminate mixture interactions. The results show that stimulating the male antenna with Z11-16:Ald and distinct plant-related odorants simultaneously suppressed pheromone-evoked activity in the region of the macroglomerular complex (MGC), where Z11-16:Ald-specific OSNs terminate. Based on our previous findings that antennal detection of Z11-16:Ald involves an interplay of the pheromone binding protein (PBP) HvirPBP2 and the pheromone receptor (PR) HR13, we asked if the plant odorants may interfere with any of the elements involved in pheromone detection. Using a competitive fluorescence binding assay, we found that the plant odorants neither bind to HvirPBP2 nor affect the binding of Z11-16:Ald to the protein. However, imaging experiments analyzing a cell line that expressed the receptor HR13 revealed that plant odorants significantly inhibited the Z11-16:Ald-evoked calcium responses. Together the results indicate that plant odorants can interfere with the signaling process of the major sex pheromone component at the receptor level. Consequently, it can be assumed that plant odorants in the environment may reduce the firing activity of pheromone-specific OSNs in H. virescens and thus affect mate localization.

In many insects, mate finding relies on female-released sex pheromones, which have to be deciphered by the male olfactory system within an odorous background of plant volatiles present in the environment of a calling female. With respect to pheromone-mediated mate localization, plant odorants may be neutral, favorable, or disturbing. Here we examined the impact of plant odorants on detection and coding of the major sex pheromone component, (Z)-11-hexadecenal (Z11-16:Ald) in the noctuid moth Heliothis virescens. By in vivo imaging the activity in the male antennal lobe (AL), we monitored the interference at the level of olfactory sensory neurons (OSN) to illuminate mixture interactions. The results show that stimulating the male antenna with Z11-16:Ald and distinct plant-related odorants simultaneously suppressed pheromone-evoked activity in the region of the macroglomerular complex (MGC), where Z11-16:Ald-specific OSNs terminate. Based on our previous findings that antennal detection of Z11-16:Ald involves an interplay of the pheromone binding protein (PBP) HvirPBP2 and the pheromone receptor (PR) HR13, we asked if the plant odorants may interfere with any of the elements involved in pheromone detection. Using a competitive fluorescence binding assay, we found that the plant odorants neither bind to HvirPBP2 nor affect the binding of Z11-16:Ald to the protein. However, imaging experiments analyzing a cell line that expressed the receptor HR13 revealed that plant odorants significantly inhibited the Z11-16:Ald-evoked calcium responses. Together the results indicate that plant odorants can interfere with the signaling process of the major sex pheromone component at the receptor level. Consequently, it can be assumed that plant odorants in the environment may reduce the firing activity of pheromone-specific OSNs in H. virescens and thus affect mate localization.

Plant odorants interfere with detection of sex pheromone signals by male Heliothis virescens

The Scn7a gene encodes for the specific sodium channel NaX, which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the NaX distribution pattern and the cell types that express NaX in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined NaX immunofluorescence with fluorescent cell markers to map and identify the NaX-expressing cell populations throughout the network involved in hydromineral homeostasis. Here, we designed an anti-NaX antibody targeting the interdomain 2–3 region of the NaX channel’s α-subunit. In both the rat and mouse, NaX immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocellular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. NaX immunostaining was also detected in neurons of the area postrema. In addition to this common NaX expression pattern, several differences in NaX immunostaining for certain structures and cell types were found between the rat and mouse. NaX was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas NaX was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, NaX immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the NaX-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. NaX expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na+ sensing are specific to each rodent species.

The Scn7a gene encodes for the specific sodium channel NaX, which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the NaX distribution pattern and the cell types that express NaX in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined NaX immunofluorescence with fluorescent cell markers to map and identify the NaX-expressing cell populations throughout the network involved in hydromineral homeostasis. Here, we designed an anti-NaX antibody targeting the interdomain 2–3 region of the NaX channel’s α-subunit. In both the rat and mouse, NaX immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocellular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. NaX immunostaining was also detected in neurons of the area postrema. In addition to this common NaX expression pattern, several differences in NaX immunostaining for certain structures and cell types were found between the rat and mouse. NaX was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas NaX was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, NaX immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the NaX-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. NaX expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na+ sensing are specific to each rodent species.

The Expression Pattern of the Na+ Sensor, NaX in the Hydromineral Homeostatic Network: A Comparative Study between the Rat and Mouse

Tastant detection in the oral cavity involves selective receptors localized at the apical extremity of a subset of specialized taste bud cells called taste receptor cells (TRCs). The identification of the genes coding for the taste receptors involved in this process have greatly improved our understanding of the molecular mechanisms underlying detection. However, how these receptors signal in TRCs, and whether the components of the signaling cascades interact with each other or are organized in complexes is mostly unexplored. Here we report on the identification of three new binding partners for the mouse G protein gamma 13 subunit (Gγ13), a component of the bitter taste receptors signaling cascade. For two of these Gγ13 associated proteins, namely GOPC and MPDZ, we describe the expression in taste bud cells for the first time. Furthermore, we demonstrate by means of a yeast two-hybrid interaction assay that the C terminal PDZ binding motif of Gγ13 interacts with selected PDZ domains in these proteins. In the case of the PDZ domain-containing protein zona occludens-1 (ZO-1), a major component of the tight junction defining the boundary between the apical and baso-lateral region of TRCs, we identified the first PDZ domain as the site of strong interaction with Gγ13. This association was further confirmed by co-immunoprecipitation experiments in HEK 293 cells. In addition, we present immunohistological data supporting partial co-localization of GOPC, MPDZ, or ZO-1, and Gγ13 in taste buds cells. Finally, we extend this observation to olfactory sensory neurons (OSNs), another type of chemosensory cells known to express both ZO-1 and Gγ13. Taken together our results implicate these new interaction partners in the sub-cellular distribution of Gγ13 in olfactory and gustatory primary sensory cells.

Tastant detection in the oral cavity involves selective receptors localized at the apical extremity of a subset of specialized taste bud cells called taste receptor cells (TRCs). The identification of the genes coding for the taste receptors involved in this process have greatly improved our understanding of the molecular mechanisms underlying detection. However, how these receptors signal in TRCs, and whether the components of the signaling cascades interact with each other or are organized in complexes is mostly unexplored. Here we report on the identification of three new binding partners for the mouse G protein gamma 13 subunit (G&#x3b3;13), a component of the bitter taste receptors signaling cascade. For two of these G&#x3b3;13 associated proteins, namely GOPC and MPDZ, we describe the expression in taste bud cells for the first time. Furthermore, we demonstrate by means of a yeast two-hybrid interaction assay that the C terminal PDZ binding motif of G&#x3b3;13 interacts with selected PDZ domains in these proteins. In the case of the PDZ domain-containing protein zona occludens-1 (ZO-1), a major component of the tight junction defining the boundary between the apical and baso-lateral region of TRCs, we identified the first PDZ domain as the site of strong interaction with G&#x3b3;13. This association was further confirmed by co-immunoprecipitation experiments in HEK 293 cells. In addition, we present immunohistological data supporting partial co-localization of GOPC, MPDZ, or ZO-1, and G&#x3b3;13 in taste buds cells. Finally, we extend this observation to olfactory sensory neurons (OSNs), another type of chemosensory cells known to express both ZO-1 and G&#x3b3;13. Taken together our results implicate these new interaction partners in the sub-cellular distribution of G&#x3b3;13 in olfactory and gustatory primary sensory cells.

Identification of new binding partners of the chemosensory signaling protein Gγ13 expressed in taste and olfactory sensory cells

Calling female moths attract their mates late at night with intermittent release of a species-specific sex-pheromone blend. Mean frequency of pheromone filaments encodes distance to the calling female. In their zig-zagging upwind search male moths encounter turbulent pheromone blend filaments at highly variable concentrations and frequencies. The male moth antennae are delicately designed to detect and distinguish even traces of these sex pheromones amongst the abundance of other odors. Its olfactory receptor neurons sense even single pheromone molecules and track intermittent pheromone filaments of highly variable frequencies up to about 30 Hz over a wide concentration range. In the hawkmoth Manduca sexta brief, weak pheromone stimuli as encountered during flight are detected via a metabotropic PLCβ-dependent signal transduction cascade which leads to transient changes in intracellular Ca2+ concentrations. Strong or long pheromone stimuli, which are possibly perceived in direct contact with the female, activate receptor-guanylyl cyclases causing long-term adaptation. In addition, depending on endogenous rhythms of the moth's physiological state, hormones such as the stress hormone octopamine modulate second messenger levels in sensory neurons. High octopamine levels during the activity phase maximize temporal resolution cAMP-dependently as a prerequisite to mate location. Thus, I suggest that sliding adjustment of odor response threshold and kinetics is based upon relative concentration ratios of intracellular Ca2+ and cyclic nucleotide levels which gate different ion channels synergistically. In addition, I propose a new hypothesis for the cyclic nucleotide-dependent ion channel formed by insect olfactory receptor/coreceptor complexes. Instead of being employed for an ionotropic mechanism of odor detection it is proposed to control subthreshold membrane potential oscillation of sensory neurons, as a basis for temporal encoding of odors.

Calling female moths attract their mates late at night with intermittent release of a species specific sex-pheromone blend. Mean frequency of pheromone filaments encodes distance to the calling female. In their zig-zagging upwind search male moths encounter turbulent pheromone blend filaments at highly variable concentrations and frequencies. The male moth antennae are delicately designed to detect and distinguish even traces of these sex pheromones amongst the abundance of other odors. Its olfactory receptor neurons sense even single pheromone molecules and track intermittent pheromone filaments of highly variable frequencies up to about 30 Hz over a wide concentration range. In the hawkmoth Manduca sexta brief, weak pheromone stimuli as encountered during flight are detected via a metabotropic PLCβ-dependent signal transduction cascade which leads to transient changes in intracellular Ca2+ concentrations. Strong or long pheromone stimuli, which are possibly perceived in direct contact with the female, activate receptor-guanylyl cyclases causing long-term adaptation. In addition, depending on endogenous rhythms of the moth’s physiological state, hormones such as the stress hormone octopamine modulate second messenger levels in sensory neurons. High octopamine levels during the activity phase maximize temporal resolution cAMP-dependently as a prerequisite to mate location. Thus, I suggest that sliding adjustment of odor response threshold and kinetics is based upon relative concentration ratios of intracellular Ca2+ and cyclic nucleotide levels which gate different ion channels synergistically. In addition, I propose a new hypothesis for the cyclic nucleotide-dependent ion channel formed by insect olfactory receptor/coreceptor complexes. Instead of being employed for an ionotropic mechanism of odor detection it is proposed to control subthreshold membrane potential oscillation of sensory neurons, as a basis for temporal encoding of odors.