Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production

Sniffing out atherosclerosis Olfactory receptors are best known for their presence in the nose and their role in detecting smells, but they are also present in other tissues and perform additional biological functions. For example, vascular macrophages involved in the pathogenesis of atherosclerosis express multiple subtypes of olfactory receptors. Orecchioni et al . focused on olfactory receptor 2, a receptor for the compound octanal, and identified its contribution to atherosclerosis pathogenesis and the formation of atherosclerotic plaques (see the Perspective by Rayner and Rasheed). The authors show that most of the octanal was not directly derived from the diet, but rather was generated as a by-product of lipid peroxidation, suggesting a potential pathway for intervention. —YN

Binding site identification of G protein-coupled receptors through a 3D Zernike polynomials-based method: application to C. elegans olfactory receptors

Studying the binding processes of G protein-coupled receptors (GPCRs) proteins is of particular interest both to better understand the molecular mechanisms that regulate the signaling between the extracellular and intracellular environment and for drug design purposes. In this study, we propose a new computational approach for the identification of the binding site for a specific ligand on a GPCR. The method is based on the Zernike polynomials and performs the ligand-GPCR association through a shape complementarity analysis of the local molecular surfaces. The method is parameter-free and it can distinguish, working on hundreds of experimentally GPCR-ligand complexes, binding pockets from randomly sampled regions on the receptor surface, obtaining an Area Under ROC curve of 0.77. Given its importance both as a model organism and in terms of applications, we thus investigated the olfactory receptors of the C. elegans, building a list of associations between 21 GPCRs belonging to its olfactory neurons and a set of possible ligands. Thus, we can not only carry out rapid and efficient screenings of drugs proposed for GPCRs, key targets in many pathologies, but also we laid the groundwork for computational mutagenesis processes, aimed at increasing or decreasing the binding affinity between ligands and receptors.

Encoding of odors by mammalian olfactory receptors

Olfactory receptors (ORs) constitute the largest multi-gene family in the mammalian genome, with hundreds to thousands of loci in humans and mice respectively. The rapid expansion of this massive family of genes has been generated by numerous duplication and diversification events throughout evolutionary history. This size, similarity, and diversity has made it challenging to define the principles by which ORs encode olfactory stimuli. Here, we performed a broad surveying of OR responses, using an in vivo strategy, against a diverse panel of odorants. We then used the resulting interaction profiles to uncover relationships between OR responses, odorants, odor molecular properties, and OR sequences. Our data and analyses revealed that ORs generally exhibited sparse tuning towards odorants and their molecular properties. Odor molecular property similarity between pairs of odorants was informative of odor response similarity. Finally, ORs sharing response to an odorant possessed amino acids at poorly conserved sites that exhibited both, predictive power towards odorant selectivity and convergent evolution. The localization of these residues occurred primarily at the interface of the upper halves of the transmembrane domains, implying that canonical positions govern odor selectivity across ORs. Altogether, our results provide a basis for translating odorants into receptor neuron responses for the unraveling of mammalian odor coding.

Hot Spot Mutagenesis Improves the Functional Expression of Unique Mammalian Odorant Receptors

Vertebrate animals detect odors through olfactory receptors (ORs), members of the G protein-coupled receptor (GPCR) family. Due to the difficulty in the heterologous expression of ORs, studies of their odor molecule recognition mechanisms have progressed poorly. Functional expression of most ORs in heterologous cells requires the co-expression of their chaperone proteins, receptor transporting proteins (RTPs). Yet, some ORs were found to be functionally expressed without the support of RTP (RTP-independent ORs). In this study, we investigated whether amino acid residues highly conserved among RTP-independent ORs improve the functional expression of ORs in heterologous cells. We found that a single amino acid substitution at one of two sites (NBW3.39 and 3.43) in their conserved residues (E and L, respectively) significantly improved the functional expression of ORs in heterologous cells. E3.39 and L3.43 also enhanced the membrane expression of RTP-dependent ORs in the absence of RTP. These changes did not alter the odorant responsiveness of the tested ORs. Our results showed that specific sites within transmembrane domains regulate the membrane expression of some ORs.

Coevolution of the olfactory organ and its receptor repertoire in ray-finned fishes

Ray-finned fishes (Actinopterygii) perceive their environment through a range of sensory modalities, including olfaction 1,2. Anatomical diversity of the olfactory organ suggests that olfaction is differentially important among species 1,3,4. To explore this topic, we studied the evolutionary dynamics of the four main gene families (OR, TAAR, ORA/VR1 and OlfC/VR2) 5 coding for olfactory receptors in 185 species of ray-finned fishes. The large variation in the number of functional genes, between 28 in the Ocean Sunfish Mola mola and 1317 in the Reedfish Erpetoichthys calabaricus, is the result of parallel expansions and contractions of the four main gene families. Several ancient and independent simplifications of the olfactory organ are associated with massive gene losses. In contrast, polypteriforms, which have a unique and complex olfactory organ, have almost twice as many olfactory receptor genes as any other ray-finned fish. These observations suggest a functional link between morphology of the olfactory organ and richness of the olfactory receptor repertoire. Further, our results demonstrate that the genomic underpinning of olfaction in ray-finned fishes is heterogeneous and presents a dynamic pattern of evolutionary expansions, simplifications and reacquisitions.

Ir76b is a Co-receptor for Amine Responses in Drosophila Olfactory Neurons

Two large families of olfactory receptors, the Odorant Receptors (ORs) and Ionotropic Receptors (IRs), mediate responses to most odors in the insect olfactory system. Individual odorant binding “tuning” OrX receptors are expressed by olfactory neurons in basiconic and trichoid sensilla and require the co-receptor Orco. The situation for IRs is more complex. Different tuning IrX receptors are expressed by olfactory neurons in coeloconic sensilla and rely on either the Ir25a or Ir8a co-receptors; some evidence suggests that Ir76b may also act as a co-receptor, but its function has not been systematically examined. Surprisingly, recent data indicate that nearly all coeloconic olfactory neurons co-express Ir25a, Ir8a, and Ir76b. Here, we demonstrate that Ir76b and Ir25a function together in all amine-sensing olfactory receptor neurons. In most neurons, loss of either co-receptor abolishes amine responses. In contrast, amine responses persist in the absence of Ir76b or Ir25a in ac1 sensilla but are lost in a double mutant. We show that responses mediated by acid-sensing neurons do not require Ir76b, despite their expression of this co-receptor. Our study also demonstrates that one population of coeloconic olfactory neurons exhibits Ir76b/Ir25a-dependent and Orco-dependent responses to distinct odorants. Together, our data establish the role of Ir76b as a bona fide co-receptor, which acts in partnership with Ir25a. Given that these co-receptors are among the most highly conserved olfactory receptors and are often co-expressed in chemosensory neurons, our data suggest Ir76b and Ir25a also work in tandem in other insects.

Cortical Hub for Flavor Sensation in Rodents

The experience of eating is inherently multimodal, combining intraoral gustatory, olfactory, and somatosensory signals into a single percept called flavor. As foods and beverages enter the mouth, movements associated with chewing and swallowing activate somatosensory receptors in the oral cavity, dissolve tastants in the saliva to activate taste receptors, and release volatile odorant molecules to retronasally activate olfactory receptors in the nasal epithelium. Human studies indicate that sensory cortical areas are important for intraoral multimodal processing, yet their circuit-level mechanisms remain unclear. Animal models allow for detailed analyses of neural circuits due to the large number of molecular tools available for tracing and neuronal manipulations. In this review, we concentrate on the anatomical and neurophysiological evidence from rodent models toward a better understanding of the circuit-level mechanisms underlying the cortical processing of flavor. While more work is needed, the emerging view pertaining to the multimodal processing of food and beverages is that the piriform, gustatory, and somatosensory cortical regions do not function solely as independent areas. Rather they act as an intraoral cortical hub, simultaneously receiving and processing multimodal sensory information from the mouth to produce the rich and complex flavor experience that guides consummatory behavior.

Olfactory Receptor OR7A17 Expression Correlates with All-Trans Retinoic Acid (ATRA)-Induced Suppression of Proliferation in Human Keratinocyte Cells

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Decoding the olfactory map: targeted transcriptomics link olfactory receptors to glomeruli

Sensory processing in olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli. Here we combined sequential sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position.

Cranial Nerves I and II

Cranial nerves I (olfactory nerve) and II (optic nerve) are supratentorial, paired cranial nerves. This chapter provides an overview of their anatomy. Cranial nerve I is a special visceral afferent nerve carrying sensory information about odors. Olfactory receptors lie in the nasal cavity. Odorants activate receptors within the cilia of olfactory sensory neurons and trigger the opening of a cyclic nucleotide–gated channel. This channel allows a calcium influx and the opening of calcium-activated chloride channels. Depolarization then occurs.