G protein-coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to the inside of the cell. They mediate the effects of various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, and are renowned drug targets. Advancements in structural biology techniques, including X-ray crystallography and cryo-electron microscopy (cryo-EM), have driven the elucidation of an increasing number of GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization and oligomerization, dichotomy between orthosteric and allosteric modulation, and the intricate interactions underlying signal transduction, providing insights into diverse ligand-binding modes and signalling pathways. However, a substantial portion of the GPCR repertoire and their activation states remain structurally unexplored. Future efforts should prioritize capturing the full structural diversity of GPCRs across multiple dimensions. To do so, the integration of structural biology with biophysical and computational techniques will be essential. We describe in this review the progress of nuclear magnetic resonance (NMR) to examine GPCR plasticity and conformational dynamics, of atomic force microscopy (AFM) to explore the spatial-temporal dynamics and kinetic aspects of GPCRs, and the recent breakthroughs in artificial intelligence for protein structure prediction to characterize the structures of the entire GPCRome. In summary, the journey through GPCR structural biology provided in this review illustrates how far we have come in decoding these essential proteins architecture and function. Looking ahead, integrating cutting-edge biophysics and computational tools offers a path to navigating the GPCR structural landscape, ultimately advancing GPCR-based applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.
- MeSH
- Protein Conformation MeSH
- Humans MeSH
- Receptors, G-Protein-Coupled * chemistry metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Alzheimerova choroba je nejčastější příčinou demence a včasná diagnostika je klíčová pro zahájení léčby. Porucha čichu, zejména schopnost identifikace pachů, byla opakovaně identifikována jako raný příznak neurodegenerativních změn a může pomoci při časné detekci Alzheimerovy choroby. Psychofyzické testy čichu, jako je Sniffin’ Sticks, (SST) University of Pennsylvania Smell Identification Test (UPSIT), či test parfémovaných fixů (OMT), jsou spolehlivými nástroji pro hodnocení čichových funkcí a mají potenciál doplnit tradiční neuropsychologické testy. Kombinace čichových a kognitivních testů významně zvyšuje přesnost predikce nástupu demence.
Koutná V, Štěpánek L, Trajerová R, Janout V, Janoutová J. Olfactory impairment as a biomarker in early diagnosis of Alzheimer’s disease in primary care Alzheimer’s disease is the most common cause of dementia and early diagnosis is key to initiating treatment. Olfactory dysfunction, particularly the ability to discriminate odors, has been repeatedly identified as an early sign of neurodegenerative changes and may aid in the early detection of Alzheimer’s disease. Psychophysical olfactory tests such as the Sniffin’ Sticks (SST), University of Pennsylvania Smell Identification Test (UPSIT) or the Odorized Marker Test (OMT) are reliable tools for assessing olfactory function and have potential to complement traditional neuropsychological tests. The combination of olfactory and cognitive tests significantly increases the accuracy of predicting the onset of dementia.
Body odors offer a unique window into the physiological and psychological profile of the emitter. This information, broadcast in nonverbal communication, significantly shapes social interactions. However, effectively digitizing body odors requires a precise framework for perceptual operationalization. Previous research has used a very limited number of verbal terms, such as pleasant, intense, or attractive, which fails to adequately capture qualitative differences. To address this gap, we elicited body odor descriptions from 2,607 participants across 17 countries and 13 languages. All these descriptions are presented here in one dataset, together with a condensed list of 25 body odor words (BOW). Those terms reliably differentiated between body states, and were validated in a separate study with a different group of 155 perceivers. The dataset, available as a web application, provides a novel operationalization of body odor impressions, which is a precondition for studying olfaction in human nonverbal communication, for perception-based digitization of body odors and for comparative studies.
Fragile X syndrome (FXS) is a neurodevelopmental disorder oftentimes associated with abnormal social behaviors and altered sensory responsiveness. It is hypothesized that the inappropriate filtering of sensory stimuli, including olfaction, can lead to aberrant social behavior in FXS. However, previous studies investigating olfaction in animal models of FXS have shown inconsistent results. Here, we found that Fmr1 knock-out (KO) mice, a mouse model of FXS, showed increased sniffing duration for non-social odors during their first exposure. Additionally, while wild-type (WT) males demonstrated differences in behavioral patterns between non-social odors while Fmr1 KO males did not show such distinction. We also showed that Fmr1 KO males spent significantly less time sniffing female urine odor compared to WT males. Moreover, we found an increased volume of the olfactory bulb in Fmr1 KO males. Overall, our findings suggest that the Fmr1 KO mice demonstrate atypical olfactory behaviors as well as structural changes in the olfactory bulb.
- MeSH
- Olfactory Bulb * metabolism MeSH
- Behavior, Animal MeSH
- Smell * physiology MeSH
- Disease Models, Animal MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Odorants * MeSH
- Fragile X Mental Retardation Protein * genetics metabolism MeSH
- Fragile X Syndrome * physiopathology genetics MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
The GPCR signalling cascade is a key pathway responsible for the signal transduction of a multitude of physical and chemical stimuli, including light, odorants, neurotransmitters and hormones. Understanding the structural and functional properties of the GPCR cascade requires direct observation of signalling processes in high spatial and temporal resolution, with minimal perturbation to endogenous systems. Optical microscopy and spectroscopy techniques are uniquely suited to this purpose because they excel at multiple spatial and temporal scales and can be used in living objects. Here, we review recent developments in microscopy and spectroscopy technologies which enable new insights into GPCR signalling. We focus on advanced techniques with high spatial and temporal resolution, single-molecule methods, labelling strategies and approaches suitable for endogenous systems and large living objects. This review aims to assist researchers in choosing appropriate microscopy and spectroscopy approaches for a variety of applications in the study of cellular signalling. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.
- MeSH
- Humans MeSH
- Microscopy * methods MeSH
- Receptors, G-Protein-Coupled * chemistry metabolism MeSH
- Signal Transduction MeSH
- Spectrum Analysis * methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Chemosensory learning is a lifelong process of acquiring perceptual expertise and semantic knowledge about chemical stimuli within the everyday environment. In the research context, it is usually simulated using olfactory training, which typically involves repeated exposure to a set of odors over a period of time. Following olfactory training, enhanced olfactory performance has been observed in adults, and similar evidence is beginning to emerge in children. However, the literature is scant concerning the effects of interventions that more closely resemble how chemosensory experience is acquired in daily life. Since children's chemosensory ecology appears to play a crucial role in olfactory development, we investigated whether engaging in activities that stimulate the chemical senses enhances olfactory performance and metacognition. To this end, we invited 20 children aged 9-11 years to participate in teacher-assisted after-school activities for 30-60 minutes a day for six weeks. During the odd weeks, the children appraised herbal and spice blends and used them to prepare dishes and make beauty products. During the even ones, they explored the city by smellwalking and created smellscape maps. The educational outcomes were evaluated using the Sniffin' Sticks test for odor identification and discrimination and the Children's Personal Significance of Olfaction. Bayesian analyses did not reveal any compelling evidence in support of the alternative hypothesis that children in the chemosensory education group outperform those in the comparison group at the post-test. Rates of reliable increase but also decrease in performance on the Sniffin' Sticks identification and discrimination tests were similar in both groups. We corroborated the previous findings regarding girls' and older children's greater proficiency at identifying odors and the female keener interest in the sense of smell. We offer several practical suggestions researchers may want to consider to tailor their research protocols to reflect more closely the broader context in which chemosensory learning takes place and better capture the nuanced outcomes of such interventions.
- MeSH
- Bayes Theorem MeSH
- Smell * physiology MeSH
- Olfactory Perception * physiology MeSH
- Child MeSH
- Humans MeSH
- Odorants * MeSH
- Schools MeSH
- Learning physiology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Olfactory sensitivity to odorant molecules is a complex biological function influenced by both endogenous factors, such as genetic background and physiological state, and exogenous factors, such as environmental conditions. In animals, this vital ability is mediated by olfactory sensory neurons (OSNs), which are distributed across several specialized olfactory subsystems depending on the species. Using the phosphorylation of the ribosomal protein S6 (rpS6) in OSNs following sensory stimulation, we developed an ex vivo assay allowing the simultaneous conditioning and odorant stimulation of different mouse olfactory subsystems, including the main olfactory epithelium, the vomeronasal organ, and the Grueneberg ganglion. This approach enabled us to observe odorant-induced neuronal activity within the different olfactory subsystems and to demonstrate the impact of environmental conditioning, such as temperature variations, on olfactory sensitivity, specifically in the Grueneberg ganglion. We further applied our rpS6-based assay to the human olfactory system and demonstrated its feasibility. Our findings show that analyzing rpS6 signal intensity is a robust and highly reproducible indicator of neuronal activity across various olfactory systems, while avoiding stress and some experimental limitations associated with in vivo exposure. The potential extension of this assay to other conditioning paradigms and olfactory systems, as well as its application to other animal species, including human olfactory diagnostics, is also discussed.
- MeSH
- Smell physiology MeSH
- Olfactory Mucosa metabolism MeSH
- Olfactory Receptor Neurons * metabolism physiology MeSH
- Phosphorylation MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Odorants analysis MeSH
- Ribosomal Protein S6 * metabolism MeSH
- Vomeronasal Organ metabolism physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Over 55 million people worldwide are living with dementia. The rate of cognitive decline increases with age, and loss of senses may be a contributing factor. OBJECTIVES: This study aimed to analyze hearing, olfactory function, and color vision in patients with dementia. MATERIALS AND METHODS: The sample comprised 40 patients with dementia and 37 cognitively normal controls aged 41-85 years. All participants underwent conventional pure-tone audiometry and a screening version of the Hearing Handicap Inventory for Adults, the Odorized Markers Test of olfactory function and the Ishihara color vision test. The effects of comorbidities and lifestyle factors were also assessed. RESULTS: Patients with dementia had significantly worse hearing at almost all frequencies tested and significantly greater olfactory impairment than cognitively normal controls. Color vision impairment was found in less than 8% of the sample, with no significant difference between the groups. Impairment of two senses (hearing and olfaction) was significantly more common in patients with dementia than in controls. CONCLUSION: Individuals with dementia were found to have sensory decline, namely hearing and olfactory impairment. Color vision was rarely impaired in the sample. Participants with dementia tended to have more multisensory impairments than controls.
- Publication type
- Journal Article MeSH
Úvod: Recentně narůstá klinický význam hodnocení čichových evokovaných potenciálů – olfactory event-related potentials (OERPs) a trigeminálních evokovaných potenciálů – trigeminal event-related potentials (TERPs) v diagnostice poruch čichu. Výhodou objektivní metody je, že OERPs jsou méně zkreslené než rutinně užívané psychofyzikální čichové testy. Klinický olfaktometr dává přesně definované čichové podněty potřebné k vyvolání OERPs a TERPs. Princip metody je založen na prezentaci odorantu pomocí speciálního zařízení v nosní dutině pacienta a registraci odpovědi mozku pomocí elektroencefalografie (EEG) na čichové a trigeminální podněty. U OERPs a TERPs hodnotíme latence a amplitudy jednotlivých peaků a intervalu N1–P2. Absence OERPs je silným prediktorem přítomnosti čichové dysfunkce. Cíl této studie: Podat první informaci o této v České republice unikátní metodě, demonstrovat OERPs a TERPs křivky u jednotlivých onemocnění spojených s poruchou čichu. Tyto výsledky budou dobrým základem pro další výzkumné projekty v oblasti poruch čichu. Metoda a materiál: V období 3/2021–6/2024 bylo do prospektivní studie zařazeno 187 subjektů (99 žen a 88 mužů). Pro měření jsme použili klinický olfaktometr OL 024 Burghart a 8kanálový EEG systém OL 026 Burghart. Výsledky: Předkládáme příkladové křivky OERPs a TERPs z jednolivých skupin zařazených subjektů: 1. skupina zařazených normosmických subjektů jsou zdraví participanti, subjekty s deviací nosního septa; 2. skupinu tvoří subjekty s chronickou rinosinusitidou s nosní polypózou; 3. skupina zahrnuje subjekty po prodělání covidu-19; 4. skupina zařazených jsou subjekty s neurodegenerativním onemocněním, s Parkinsonovou chorobou, s roztroušenou sklerózou; 5. skupina zahrnuje subjekty s tumory vedlejších nosních dutin, olfaktorní oblasti, hypofýzy; 6. skupina je tvořena subjekty s poruchou čichu, které byly indikovány k vyšetření z mediko-legálních důvodů; 7. skupinou jsou zařazené subjekty s poúrazovou ztráta čichu. Závěr: Jsou demonstrovány příkladové křivky OERPs a TERPs. Získaná data mohou být velmi dobře aplikována v budoucnu jako vnitřní vodítko pro naše další probíhající výzkumné studie čichu. Absence čichových evokovaných potenciálů je silným prediktorem přítomnosti čichové dysfunkce. Objektivní olfaktometrie se jeví jako metoda s narůstajícím potenciálem, a to hlavně u osob, které obtížně zvládají běžně dostupné psychofyzické testování čichu, u pacientů s neurodegenerativním onemocněním, a v oblasti lékařsko-pracovně-právní.
Introduction: The clinical importance of olfactory evoked potentials (OERPs) and trigeminal evoked potentials (TERPs) in the diagnosis of olfactory disorders has recently increased. The advantage of the objective method is that OERPs are less biased than routinely used psychophysical olfactory tests. The clinical olfactometer gives precisely defined olfactory stimuli needed to elicit OERPs and TERPs. The principle of the method is based on the presentation of an odorant by a special device in the patient‘s nasal cavity and the registration of the brain response by electroencephalography (EEG) to the olfactory and trigeminal stimuli. For OERPs and TERPs, we evaluate the latencies and amplitudes of individual peaks and the N1–P2 interval. The absence of OERPs is a strong predictor of the presence of olfactory dysfunction. Aim of this study: These data will be a good basis for further research projects in the field of olfactory disorders. Materials and methods: Between 3/2021 and 6/2024, 187 subjects (99 females and 88 males) were enrolled in a prospective study. A clinical olfactometer OL 024 Burghart and an 8-channel EEG system OL 026 Burghart were used for measurements. Results: We present sample OERPs and TERPs curves from single groups of enrolled subjects. The 1st group of normosmic subjects – healthy participants, subjects with a deviation of the nasal septum. The 2nd group consists of subjects with chronic rhinosinusitis with nasal polyposis. The 3rd group includes subjects after undergoing COVID-19. The 4th group of enrolees are subjects with neurodegenerative disease, Parkinson‘s disease, and multiple sclerosis. The 5th group includes subjects with tumors of the paranasal sinuses, olfactory region, and pituitary gland. The 6th group consists of subjects with olfactory disorders who were indicated for examination for medico-legal reasons. The 7th group consists of subjects with post-traumatic loss of smell. Conclusion: Sample OERPs and TERPs curves are demonstrated. The data obtained may very well be applied in the future as an internal guide for our other ongoing olfaction research studies. The absence of olfactory evoked potentials is a robust predictor of the presence of olfactory dysfunction. Objective olfactometry appears to be a method with increasing potential, especially in persons who have difficulty with commonly available psychophysical testing of the sense of smell, in patients with neurodegenerative disease, and in the medicolegal field.
- Keywords
- čichové evokované potenciály, trigeminální evokované potenciály,
- MeSH
- Evoked Potentials * MeSH
- Humans MeSH
- Odorants MeSH
- Olfactometry * methods MeSH
- Olfaction Disorders diagnostic imaging MeSH
- Prospective Studies MeSH
- Evoked Potentials, Somatosensory MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
Research shows that male body odor plays an important role in women's mate choice and that olfactory abilities are associated with women's sexual functioning. What remains unclear is what types of partner's odor actually shape women's experience during intimate activities. This study therefore explored women's experience associated with the partner's various odors and investigated how they affect women's intimate and sexual encounters. We performed semi-structured individual interviews with 20 single women and 20 women in a long-term relationship. Thematic analysis revealed four key natural odor types of the partner: body odor, sweat, genital odor, and semen odor. Further, we have identified three main types of fragrance odor (cologne, shower gel, and laundry agents) and investigated their perception in both intimate (hugging, kissing, cuddling, lying side by side) and sexual (intercourse, oral sex, ejaculation) contexts. Both partner's natural odor and fragrance affected women's emotional state (ranging from pleasant to unpleasant) and behavioral response (ranging from approach to avoidance of partner). Women's odor perception was frequently context-dependent, so that even mostly negatively perceived odors (e.g., semen, genital odor) were often accepted as part of sexual encounter. Finally, women's perception was negatively modified by partner's specific sweat (after workday, workout, or when the partner is ill) during intimate encounters. Our results highlight the complexity and interindividual variability of partner's odor perception.
- MeSH
- Smell physiology MeSH
- Olfactory Perception physiology MeSH
- Adult MeSH
- Interpersonal Relations MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Odorants * MeSH
- Sweat MeSH
- Sexual Behavior * psychology MeSH
- Sexual Partners * psychology MeSH
- Semen MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
