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    • br ACKNOWLEDGMENTS br Introduction Odorant

    2022-01-13


    ACKNOWLEDGMENTS
    Introduction Odorant receptors (ORs) are the largest subfamily of G protein-coupled receptors (GPCRs) and are mainly expressed by olfactory sensory neurons in the nose for the detection of various odorants [1]. However, more recent reports suggest that ORs are also expressed and function in nonolfactory tissues [2,3]. The first ectopic ORs were discovered in testis in 1992 [4] and have since been identified in kidney [5], carotid body [6], heart [7], bladder, thyroid, testis [8], pancreas [9], muscle [10], and skin [11]. However, little is known about OR expression in the 50014 sale [12,13]. The brain comprises neurons and glial cells [14], the latter of which account for a more substantial portion [15] and of which 20–40% are star-shaped cells called astrocytes [16]. Although GPCR expression and its function in astrocytes are well known [17,18], there have been no reports on the presence of ORs, the largest family of GPCRs, in astrocytes. The ligands for GPCRs, such as GPR41 and GPR43, include short-chain fatty acids (SCFAs) of one to six carbons [19]. Recent studies show that SCFAs regulate the maturation of microglia in the brain [20]. SCFAs also act as ligands for ORs. For example, microbiota-derived acetate and propionate are ligands for Olfr78/OR51E2 expressed in the kidney to regulate renin secretion and blood pressure [5].
    Materials and methods
    Results
    Discussion The results of this study demonstrate that cortical astrocytes express the OR Olfr920 and identify IBA as a ligand. IBA is a metabolite produced by plants, such as carrots and vanilla [29], as well as by periodontal pathogens, such as Porphyromonas gingivalis and Fusobacterium nucleatum [30]. Humans are primarily exposed to IBA through ingestion, and IBA can be detected in blood, cerebrospinal fluid, feces, and urine [31]. The concentration of IBA in the saliva of patients with severe periodontal disease increases by several hundred micromolar compared with that of healthy participants [30]. Thus, the EC50 value of 241.2 μM for Olfr920 measured in the present study suggests that IBA likely activates target ORs in vivo. Additional studies are required to determine the physiological concentration of IBA in the brain to confirm the physiological activation of astrocytes. The activation of Olfr920 in cortical astrocytes by IBA resulted in the production of cAMP. LPS treatment also increases cAMP levels [32] as well as GFAP expression [33] in astrocytes. However, LPS has also been shown to activate toll-like receptor 4, resulting in decreased cAMP levels [34]. The results of the present study revealed that IBA increased cAMP levels in astrocytes but, surprisingly, blocked the induction of GFAP in reactive astrocytes expressing Olfr920. Thus, the induction of GFAP by LPS needs further investigation, particularly to characterize the downstream crosstalk between IBA and LPS in reactive astrocytes. Of note, GFAP expression is increased with CNS trauma, by hypoxia, around growing tumors, and in many neurodegenerative conditions [35,36]. The results presented here suggest that Olfr920 is a novel target to potentially suppress reactive astrocytosis.
    Acknowledgment This research was supported by the DGIST R&D Program of the Ministry of Science, ICT, and Future Planning (19-BT-02).
    Introduction The free fatty acid receptor 1 (FFA1, known as GPR40 prior to its de-orphaning in 2003) promptly became a biological target of high importance from the standpoint of developing fundamentally new therapeutic agents against type 2 diabetes mellitus (T2DM). FFA1 agonists are capable of raising insulin levels but only do so in hyperglycemic state when the FFA1 expression is upregulated. The activation of FFA1 triggers a GPCR signaling cascade which invokes insulin secretion to normalize blood glucose levels. As a result, the expression of the receptor goes back to normal, desensitizing the insulin-producing machinery to FFA1 agonists still remaining in circulation. This is in sharp contrast to other antidiabetic agents, such as sulfonylureas, that continue stimulating insulin release irrespective of the current glucose levels and can, therefore, cause hypoglycemia (an adverse, potentially deadly condition).