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Perception of biotic and abiotic stresses often leads to stomatal closure in plants 1 , 2 . Rapid influx of calcium ions (Ca 2+ ) across the plasma membrane has an important role in this response, but the identity of the Ca 2+ channels involved has remained elusive 3 , 4 . Here we report that the Arabidopsis thaliana Ca 2+ -permeable channel OSCA1.3 controls stomatal closure during immune signalling. OSCA1.3 is rapidly phosphorylated upon perception of pathogen-associated molecular patterns (PAMPs). Biochemical and quantitative phosphoproteomics analyses reveal that the immune receptor-associated cytosolic kinase BIK1 interacts with and phosphorylates the N-terminal cytosolic loop of OSCA1.3 within minutes of treatment with the peptidic PAMP flg22, which is derived from bacterial flagellin. Genetic and electrophysiological data reveal that OSCA1.3 is permeable to Ca 2+ , and that BIK1-mediated phosphorylation on its N terminus increases this channel activity. Notably, OSCA1.3 and its phosphorylation by BIK1 are critical for stomatal closure during immune signalling, and OSCA1.3 does not regulate stomatal closure upon perception of abscisic acid—a plant hormone associated with abiotic stresses. This study thus identifies a plant Ca 2+ channel and its activation mechanisms underlying stomatal closure during immune signalling, and suggests specificity in Ca 2+ influx mechanisms in response to different stresses. A study in Arabidopsis thaliana shows that the immune receptor-associated cytosolic kinase BIK1 phosphorylates OSCA1.3 and identifies OSCA1.3 as the pathogen-responsive Ca 2+ -permeable channel that regulates stomatal closure.

Vitamin D deficiency affects approximately 80% of individuals in some countries and has been linked with gut dysbiosis and inflammation. While the benefits of vitamin D supplementation on the gut microbiota have been studied in patients with chronic diseases, its effects on the microbiota of otherwise healthy individuals is unclear. Moreover, whether effects on the microbiota can explain some of the marked inter-individual variation in responsiveness to vitamin D supplementation is unknown. Here, we administered vitamin D to 80 otherwise healthy vitamin D-deficient women, measuring serum 25(OH) D levels in blood and characterizing their gut microbiota pre- and post- supplementation using 16S rRNA gene sequencing. Vitamin D supplementation significantly increased gut microbial diversity. Specifically, the Bacteroidetes to Firmicutes ratio increased, along with the abundance of the health-promoting probiotic taxa Akkermansia and Bifidobacterium. Significant variations in the two-dominant genera, Bacteroides and Prevotella , indicated a variation in enterotypes following supplementation. Comparing supplementation responders and non-responders we found more pronounced changes in abundance of major phyla in responders, and a significant decrease in Bacteroides acidifaciens in non-responders. Altogether, our study highlights the positive impact of vitamin D supplementation on the gut microbiota and the potential for the microbial gut signature to affect vitamin D response.

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study. Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.

Vitamin D has a key role in stimulating calcium absorption from the gut and promoting skeletal health, as well as many other important physiological functions. Vitamin D is produced in the skin. It is subsequently metabolized to its hormonally active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), by the 1-hydroxylase and catabolized by the 24-hydroxylase. In this Review, we pay special attention to the effect of mutations in these enzymes and their clinical manifestations. We then discuss the role of vitamin D binding protein in transporting vitamin D and its metabolites from their source to their targets, the free hormone hypothesis for cell entry and HSP70 for intracellular transport. This is followed by discussion of the vitamin D receptor (VDR) that mediates the cellular actions of 1,25(OH)2D. Cell-specific recruitment of co-regulatory complexes by liganded VDR leads to changes in gene expression that result in distinct physiological actions by 1,25(OH)2D, which are disrupted by mutations in the VDR. We then discuss the epidermis and hair follicle, to provide a non-skeletal example of a tissue that expresses VDR that not only makes vitamin D but also can metabolize it to its hormonally active form. This enables vitamin D to regulate epidermal differentiation and hair follicle cycling and, in so doing, to promote barrier function, wound healing and hair growth, while limiting cancer development.This Review provides an overview of vitamin D production in the skin. The regulation of wound healing and hair growth by vitamin D are also discussed.

Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion. Elevated inorganic phosphate levels promote excessive parathyroid hormone secretion, which contributes to the aetiology of secondary hyperparathyroidism. Here, the authors show that phosphate directly inhibits the calcium-sensing receptor, the main regulator of parathyroid hormone secretion.

Different cell channels and transporters tightly regulate cytoplasmic levels and the intraorganelle distribution of cations. Perturbations in these processes lead to human diseases that are frequently associated with kidney impairment. The family of melastatin-related transient receptor potential (TRPM) channels, which has eight members in mammals (TRPM1–TRPM8), includes ion channels that are highly permeable to divalent cations, such as Ca2+, Mg2+ and Zn2+ (TRPM1, TRPM3, TRPM6 and TRPM7), non-selective cation channels (TRPM2 and TRPM8) and monovalent cation-selective channels (TRPM4 and TRPM5). Three family members contain an enzymatic protein moiety: TRPM6 and TRPM7 are fused to α-kinase domains, whereas TRPM2 is linked to an ADP-ribose-binding NUDT9 homology domain. TRPM channels also function as crucial cellular sensors involved in many physiological processes, including mineral homeostasis, blood pressure, cardiac rhythm and immunity, as well as photoreception, taste reception and thermoreception. TRPM channels are abundantly expressed in the kidney. Mutations in TRPM genes cause several inherited human diseases, and preclinical studies in animal models of human disease have highlighted TRPM channels as promising new therapeutic targets. Here, we provide an overview of this rapidly evolving research area and delineate the emerging role of TRPM channels in kidney pathophysiology.The family of melastatin-like transient receptor potential (TRPM) channels comprises eight multifunctional cation channels. Here, the authors examine the functional role of each TRPM channel, including insights from channelopathies, and discuss the implications for kidney homeostasis and pathology.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca 2+ -mobilizing second messenger which uniquely mobilizes Ca 2+ from acidic endolysosomal organelles. However, the molecular identity of the NAADP receptor remains unknown. Given the necessity of the endolysosomal two-pore channel (TPC1 or TPC2) in NAADP signaling, we performed affinity purification and quantitative proteomic analysis of the interacting proteins of NAADP and TPCs. We identified a Sm-like protein Lsm12 complexed with NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and immediately participates in NAADP-evoked TPC activation and Ca 2+ mobilization from acidic stores. These findings reveal a putative RNA-binding protein to function as an NAADP receptor and a TPC regulatory protein and provides a molecular basis for understanding the mechanisms of NAADP signaling. Nicotinic acid adenine dinucleotide phosphate (NAADP) potent Ca 2+ mobilizing second messenger which uniquely triggers Ca 2+ release from acidic endolysosomal organelles. Here the authors identify Lsm12 as an NAADP receptor essential for NAADP-evoked Ca 2+ release from lysosomes via NAADP binding on its Lsm domain.

Key Points Modern humans can expect to live a long life and therefore need to make a balanced choice between exposure to carcinogenic UVB radiation and maintaining an optimal vitamin D status Most countries and many scientific societies have prepared or updated guidelines for vitamin D supplementation, with recommended dosages higher than before All infants need a daily supplement of vitamin D (preferably 400 international units (IU) per day) during at least their first year of life; however, full implementation of this guideline is problematic in many countries around the world A large consensus exists that nearly all elderly individuals need a vitamin D supplement; however, disagreement endures with regard to dosage or optimal concentration of 25-hydroxyvitamin D, and implementation is problematic All children or adults lacking sufficient exposure to sunlight need a vitamin D supplement; however, no agreement has been reached regarding dosage, and implementation is poor The WHO, supported by its member states, should implement a strategy to eradicate vitamin D (and calcium) deficiency-associated rickets Governments and scientific societies regularly update recommendations for intake of vitamin D, especially for those individuals who have limited exposure to sunlight — the main source of vitamin D. Here, Roger Bouillon presents an overview of these guidelines, highlighting common ground and areas of discord. Vitamin D is essential for calcium and bone homeostasis. Humans are largely dependent on UVB-radiation-induced photosynthesis of vitamin D, as few foods contain vitamin D. However, the same radiation that produces vitamin D is also carcinogenic, albeit with a long lag time, and causes DNA damage. In view of the increasing life expectancy, avoiding excessive sun exposure is prudent. Several groups of people have a shortfall between their requirements for vitamin D and their combined endogenous synthesis and intake from natural foods, and therefore need vitamin D supplementation. Governments and scientific societies are regularly updating their recommendations for intake of vitamin D, especially for groups that should (infants) or prefer to (especially elderly individuals) avoid direct sunlight. An overview of such guidelines is presented in this Review. A fairly large consensus exists that all infants should receive 400 international units (IU) (10 μg) daily during their first year of life and that elderly individuals should have access to vitamin D supplementation (at recommended dosages varying from 400 IU to 800 IU daily in most governmental guidelines but at higher dosages in other guidelines). All guidelines unanimously agree that serum levels of 25-hydroxyvitamin D (25OHD) <25 nmol/l (10 ng/ml) should be avoided at all ages. Children and adults who have limited sun exposure should receive vitamin D supplementation, but the recommended doses vary widely (from 200 IU to 2,000 IU daily), in line with disagreement regarding the minimal desirable serum concentration of 25OHD (which varies from 25 nmol/l to >100 nmol/l).

Hyperglycemia in diabetes mellitus (DM) patients is a causative factor for amyloidogenesis and induces neuropathological changes, such as impaired neuronal integrity, neurodegeneration, and cognitive impairment. Regulation of mitochondrial calcium influx from the endoplasmic reticulum (ER) is considered a promising strategy for the prevention of mitochondrial ROS (mtROS) accumulation that occurs in the Alzheimer’s disease (AD)-associated pathogenesis in DM patients. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A has received an increasing amount of attention as a novel candidate with anti-oxidative and neuroprotective effects in AD. Here, we investigated the effect of urolithin A on high glucose-induced amyloidogenesis caused by mitochondrial calcium dysregulation and mtROS accumulation resulting in neuronal degeneration. We also identified the mechanism related to mitochondria-associated ER membrane (MAM) formation. We found that urolithin A-lowered mitochondrial calcium influx significantly alleviated high glucose-induced mtROS accumulation and expression of amyloid beta (Aβ)-producing enzymes, such as amyloid precursor protein (APP) and β-secretase-1 (BACE1), as well as Aβ production. Urolithin A injections in a streptozotocin (STZ)-induced diabetic mouse model alleviated APP and BACE1 expressions, Tau phosphorylation, Aβ deposition, and cognitive impairment. In addition, high glucose stimulated MAM formation and transglutaminase type 2 (TGM2) expression. We first discovered that urolithin A significantly reduced high glucose-induced TGM2 expression. In addition, disruption of the AIP–AhR complex was involved in urolithin A-mediated suppression of high glucose-induced TGM2 expression. Markedly, TGM2 silencing inhibited inositol 1, 4, 5-trisphosphate receptor type 1 (IP3R1)–voltage-dependent anion-selective channel protein 1 (VDAC1) interactions and prevented high glucose-induced mitochondrial calcium influx and mtROS accumulation. We also found that urolithin A or TGM2 silencing prevented Aβ-induced mitochondrial calcium influx, mtROS accumulation, Tau phosphorylation, and cell death in neuronal cells. In conclusion, we suggest that urolithin A is a promising candidate for the development of therapies to prevent DM-associated AD pathogenesis by reducing TGM2-dependent MAM formation and maintaining mitochondrial calcium and ROS homeostasis.

Osteoporosis is characterized by low bone mass and microarchitecture deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk. Evidence is accumulating for an important role of calcium deficiency as the process of aging is associated with disturbed calcium balance. Vitamin D is the principal factor that maintains calcium homeostasis. Increasing evidence indicates that the reason for disturbed calcium balance with age is inadequate vitamin D levels in the elderly. In this article, an overview of our current understanding of vitamin D, its metabolism, and mechanisms involved in vitamin D-mediated maintenance of calcium homeostasis is presented. In addition, mechanisms involved in age-related dysregulation of 1,25（OH）2D3 action, recommended daily doses of vitamin D and calcium, and the use of vitamin D analogs for the treatment of osteoporosis （which remains controversial） are reviewed. Elucidation of the molecular pathways of vitamin D action and modifications that occur with aging will be an active area of future research that has the potential to reveal new therapeutic strategies to maintain calcium balance.