Biology subjects

Matsunami, H.

Publications and source records attributed to Matsunami, H..

25 records · Page 2Linked to original sources

bioRxiv2019

Comparative genomic analysis of the pheromone receptor Class 1 family (V1R) reveals extreme complexity in mouse lemurs (genus, Microcebus) and chromosomal hotspots across mammals

Sensory gene families are of special interest, both for what they can tell us about molecular evolution, and for what they imply as mediators of social communication. The vomeronasal type-1 receptors (V1Rs) have often been hypothesized as playing a fundamental role in driving or maintaining species boundaries given their likely function as mediators of intraspecific mate choice, particularly in nocturnal mammals. Here, we employ a comparative genomic approach for revealing patterns of V1R evolution within primates, with a special focus on the small-bodied nocturnal mouse and dwarf lemurs of Madagascar (genera Microcebus and Cheirogaleus, respectively). By doubling the existing genomic resources for strepsirrhine primates (i.e., the lemurs and lorises), we find that the highly-speciose and morphologically-cryptic mouse lemurs have experienced an elaborate proliferation of V1Rs that we argue is functionally related to their capacity for rapid lineage diversification. Contrary to a previous study that found equivalent degrees of V1R diversity in diurnal and nocturnal lemurs, our study finds a strong correlation between nocturnality and V1R elaboration, with nocturnal lemurs showing elaborate V1R repertoires and diurnal lemurs showing less diverse repertoires. Recognized subfamilies among V1Rs show unique signatures of diversifying positive selection, as might be expected if they have each evolved to respond to specific stimuli. Further, a detailed syntenic comparison of mouse lemurs with mouse (genus Mus) and other mammalian outgroups shows that orthologous mammalian subfamilies, predicted to be of ancient origin, tend to cluster in a densely populated region across syntenic chromosomes that we refer to as V1R \"hotspots.\"

genomics↗

bioRxiv2019

Synergetic influence of beta-caryophyllene on wound healing

Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices. Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses. We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization. The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta-caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene. Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.

physiology↗

bioRxiv2019

Divergence from conserved residues underlies intracellular retention of mammalian odorant receptors

Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in non-olfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here, we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing "consensus" odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations. Significance StatementOdor detection in mammals depends on the largest family of G protein-coupled receptors, the odorant receptors, which represent [~]2% of our protein-coding genes. The vast majority of odorant receptors are trapped within the cell when expressed in non-olfactory cells. The underlying causes of why odorant receptors cannot be functionally expressed in non-olfactory cells have remained enigmatic for over 20 years. Our study points to divergence from a consensus sequence as a key factor in a receptors inability to function in non-olfactory cells, which in turn, helps explain odorant receptors exceptional functional diversity and rapid evolution. We also show the success of protein engineering strategies for promoting odorant receptor cell surface expression.

cell biology↗

bioRxiv2018

A Scalable, Multiplexed Assay for Decoding Receptor-Ligand Interactions

Chemicals such as drugs, hormones, and odorants can have many potential interactions with endogenous targets, and uncovering these relationships is critical for understanding and modulating function. Mammalian olfactory receptors (ORs), a large family of G protein-coupled receptors, mediate olfaction through activation by small molecules. Each OR can respond to many odorants, and vice versa, making exploring this space one interaction at a time difficult. We developed a high-throughput receptor screening platform in human cell lines to screen libraries of chemicals against a multiplexed library of receptors using next-generation sequencing of barcoded genetic reporters. We screened three concentrations of 181 odorants, where in each well we record the activity of 39 ORs simultaneously, and identified 79 novel associations, including ligands for 15 orphan receptors. This platform allows the cost-effective mapping of large chemical libraries to receptor repertoires at scale.

biochemistry↗

bioRxiv2018

Olfactory and Vomeronasal Receptor Feedback Employ Divergent Mechanisms of PERK Activation

Mutually-exclusive chemoreceptor expression in olfactory and vomeronasal sensory neurons (OSNs and VSNs) enables odorant discrimination. This configuration involves chemoreceptor mediated activation of the endoplasmic reticulum (ER)-resident kinase PERK. PERK drives translation of the transcription factor ATF5 to preclude additional chemoreceptor expression. ATF5 translation is transient in OSNs but persistent in VSNs, suggesting chemoreceptor-specific modes of PERK activation. Herein, we showed that the ER-lumenal domain (LD) of PERK recognized vomeronasal receptor (VR)-derived peptides, suggesting direct PERK activation drives persistent ATF5 translation in VSNs. In contrast, PERK LD did not recognize olfactory receptor (OR)-derived peptides in vitro, and facilitating OR maturation in vivo prevented PERK activation, suggesting that ORs activate PERK indirectly through a failure to exit the ER. Importantly, impairing or prolonging ATF5 expression drove specific chemoreceptor repertoire biases. Together, these results demonstrate mechanistic divergence in chemoreceptor feedback and establish that differences in PERK activation promote qualitatively different gene regulatory results.

cell biology↗

bioRxiv2018

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer but its function is not well understood. Through in silico and in vitro analyses, we identified 24 agonists and 1 antagonist for this receptor. We detected that agonist 19-hydroxyandrostenedione, a product of the aromatase reaction, is endogenously produced upon receptor activation. We characterized the effects of receptor activation on metabolism using a prostate cancer cell line and demonstrated decreased intracellular anabolic signals and cell viability, induction of cell cycle arrest, and increased expression of neuronal markers. Furthermore, upregulation of neuron-specific enolase by agonist treatment was abolished in OR51E2-KO cells. The results of our study suggest that OR51E2 activation results in neuroendocrine trans-differentiation. These findings reveal a new role for OR51E2 and establish this G-protein coupled receptor as a novel therapeutic target in the treatment of prostate cancer.\n\nSignificanceProstate cancer is the second most common cancer in men. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer characterized by increased number of neuroendocrine-like cells. These neuroendocrine-like cells are non-proliferating, terminally differentiated cells. Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer, and its expression correlates with disease progression. Here, we identify and validate novel endogenous ligands for this receptor. We show that activation of OR51E2 by newly-discovered prostate cancer-relevant agonists facilitates cellular transformation, resulting in neuroendocrine trans-differentiation, a characteristic phenotype of castrate resistant prostate cancer. Our results establish this G-protein coupled receptor as a novel and therapeutic target for castration-resistant prostate cancer.\n\nHighlightsO_LIDiscovery of novel agonists for olfactory receptor OR51E2/PSGR highly relevant to prostate cancer pathology\nC_LIO_LIActivation of OR51E2 receptor by agonist N-acetyl-N-formyl-5-methoxykynurenamine (AFMK) results in release of 19-hydroxyandrostenedione (19-OH AD) from the prostate cancer cells indicating its endogenous production\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD, AFMK, and propionic acid decreases anabolic and proliferative signals\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD and AFMK increases markers specific for neuroendocrine trans-differentiation (NEtD)\nC_LIO_LIAblation of the OR51E2 gene in prostate cancer cells treated with agonist 19-OH AD significantly reduces neuron-specific enolase\nC_LI

cancer biology↗

bioRxiv2017

Genetic variation across the human olfactory receptor repertoire alters odor perception

The human olfactory receptor repertoire is characterized by an abundance of genetic variation that affects receptor response, but the perceptual effects of this variation are unclear. To address this issue, we sequenced the OR repertoire in 332 individuals and examined the relationship between genetic variation and 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR frequently associated with odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. This more than doubles the published examples of this phenomenon. For eight of these 10 cases, reduced receptor function associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age and gender, we can explain between 10 and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in variation of olfactory perception.

genetics↗