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Abstract Objectives GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. Methods and results We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity. Conclusions GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon. Highlights • GPR142 functions as a selective sensor of aromatic amino acids. • GPR142 stimulates GIP, CCK and GLP-1 with GIP being particularly sensitive. • GPR142 stimulates insulin and glucagon and improves glucose tolerance. • The glucagon-mediated hepatic component of GPR142 action is significant. • Chronic GPR142 treatment increases insulin sensitivity and energy expenditure. [ABSTRACT FROM AUTHOR]

Using the method of adsorption spectroscopy, the temperature dependence of the electronic absorption spectra of the fluorescent chemosensor (CS), based on the supramolecular pyrene-2β-cyclodextrin complex (Pyr@2βCD, PCD), was studied in the absence and in the presence of phenylalanine (Phe). The application of CS, where pyrene serves as a fluorescent probe, is based on the ability of CS to form the inclusion complexes with small organic molecules as well as with aromatic amino acids (AA) such as Phe, tryptophan (Trp), tyrosine (Tyr), and histidine (His) in aqueous solutions. Upon heating to 55 °C, the PCD complex in the presence of Phe shows a higher stability as compared to that in the absence of Phe. The molecular dynamics simulation was applied to study the thermal stability of PCD and its complexes with the above AAs in water. The PCD complex exists in two configurations. In configuration 1 the planar Pyr molecule lies in the equatorial plane of the βCD dimer, the plane of Pyr is nearly perpendicular to the vertical axis of the dimer 2βCD, and water fills up the empty part of the cavity. In configuration 2, the plane of Pyr is inclined with respect to the axis of the 2βCD dimer by ~30°. The PCD complex initially prepared in state 1 is spontaneously transformed into state 2 and remains stable up to the boiling temperature. The transition of PCD from the form 1 to 2 is provided by fluctuations in water content in its cavities. The inclusion complexes of amino acids 2AA@PCD exist in a single conformation 1. Complexes of PCD with Trp and Phe are stable up to the boiling temperature, i.e., these AAs are preserved within the PCD cavities even at the elevated temperature. The complex with Tyr decays at 60 °C, and the complex with His is unstable at room temperature and above. [ABSTRACT FROM AUTHOR]

Synthetic toxic chemicals (toxicants) and biological poisons (toxins) have been developed as chemical warfare agents in the last century. At the time of their initial consideration as chemical weapon, only restricted knowledge existed about their mechanisms of action. There exist two different types of acute toxic action: nonspecific cytotoxic mechanisms with multiple chemo-biological interactions versus specific mechanisms that tend to have just a single or a few target biomolecules. TRPV1- and TRPA-receptors are often involved as chemosensors that induce neurogenic inflammation. The present work briefly surveys classes and toxicologically relevant features of chemical warfare agents and describes mechanisms of toxic action. [ABSTRACT FROM AUTHOR]

Background Studies in rheumatoid arthritis synovial fibroblasts (RASF) demonstrated the expression of several transient receptor potential channels (TRP) such as TRPV1, TRPV2, TRPV4, TRPA1 and TRPM8. Upon ligation, these receptors increase intracellular calcium but they have also been linked to modulation of inflammation in several cell types. TNF was shown to increase the expression of TRPA1, the receptor for mustard oil and environmental poisons in SF, but the functional consequences have not been investigated yet. Methods TRPA1 was detected by immunocytochemistry, western blot and cell-based ELISA. Calcium measurements were conducted in a multimode reader. Cell viability was assessed by quantification of lactate dehydrogenase (LDH) in culture supernatants and “RealTime-Glo” luminescent assays. IL-6 and IL-8 production by SF was quantified by ELISA. Proliferation was determined by cell titer blue incorporation. Results After 72 h, mimicking proinflammatory conditions by the innate cytokine TNF up-regulated TRPA1 protein levels in RASF which was accompanied by increased sensitivity to TRPA1 agonists AITC and polygodial. Under unstimulated conditions, polygodial elicited calcium flux only in the highest concentrations used (50 µM and 25 µM). TNF preincubation substantially lowered the activation threshold for polygodial (from 25 µM to 1 µM). In the absence of TNF pre-stimulation, only polygodial in high concentrations was able to reduce viability of synovial fibroblasts as determined by a real-time viability assay. However, following TNF preincubation, stimulation of TRPA1 led to a fast (<30 min) viability loss by necrosis of synovial fibroblasts. TRPA1 activation was also associated with decreased proliferation of RASFs, an effect that was also substantially enhanced by TNF preincubation. On the functional level, IL-6 and IL-8 production was attenuated by the TRPA1 antagonist A967079 but also polygodial, although the latter mediated this effect by reducing cell viability. Conclusion Simulating inflamed conditions by preincubation of synovial fibroblasts with TNF up-regulates and sensitizes TRPA1. Subsequent activation of TRPA1 increases calcium flux and substantially reduces cell viability by inducing necrosis. Since TRPA1 agonists in the lower concentration range only show effects in TNF-stimulated RASF, this cation channel might be an attractive therapeutic target in chronic inflammation to selectively reduce the activity of proinflammatory SF in the joint. [ABSTRACT FROM AUTHOR]

Dystrophin is a cytoskeleton-linked membrane protein that binds to a larger multiprotein assembly called the dystrophin-associated glycoprotein complex (DGC). The deficiency of dystrophin or the components of the DGC results in the loss of connection between the cytoskeleton and the extracellular matrix with significant pathophysiological implications in skeletal and cardiac muscle as well as in the nervous system. Although the DGC plays an important role in maintaining membrane stability, it can also be considered as a versatile and flexible molecular complex that contribute to the cellular organization and dynamics of a variety of proteins at specific locations in the plasma membrane. This review deals with the role of the DGC in transmembrane signaling by forming supramolecular assemblies for regulating ion channel localization and activity. These interactions are relevant for cell homeostasis, and its alterations may play a significant role in the etiology and pathogenesis of various disorders affecting muscle and nerve function. [ABSTRACT FROM AUTHOR]

The resolution of acute inflammation, once thought to be a passive process, is now recognized as an active one. The productions of endogenous special proresolving mediators (SPMs) are involved in this process. SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated from ω-6 arachidonic acid or ω-3 poly-unsaturated fatty acids during the resolution phase of acute inflammation. They have potent anti-inflammatory and proresolving actions in various inflammatory disorders. Due to the potent proresolving and anti-inflammatory effects, SPMs are also used for pain relief. This review focuses on the mechanisms by which SPMs act on their respective G-protein-coupled receptors in immune cells and nerve cells to normalize pain via regulating inflammatory mediators, transient receptor potential ion channels, and central sensitization. SPMs may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation. [ABSTRACT FROM AUTHOR]

Key points: Mutagenesis at positively charged amino acids (arginines and lysines) (R1–R4) in the voltage‐sensor domain (transmembrane segment (S) 4) of voltage‐gated Na+, K+ and Ca2+ channels can lead to an alternative ion permeation pathway distinct from the central pore. Recently, a non‐canonical ion permeation pathway was described in TRPM3, a member of the transient receptor potential (TRP) superfamily. The non‐canonical pore exists in the native TRPM3 channel and can be activated by co‐stimulation of the endogenous agonist pregnenolone sulphate and the antifungal drug clotrimazole or by stimulation of the synthetic agonist CIM0216. Alignment of the voltage sensor of Shaker K+ channels with the entire TRPM3 sequence revealed the highest degree of similarity in the putative S4 region of TRPM3, and suggested that only one single gating charge arginine (R2) in the putative S4 region is conserved. Mutagenesis studies in the voltage‐sensing domain of TRPM3 revealed several residues in the voltage sensor (S4) as well as in S1 and S3 that are crucial for the occurrence of the non‐canonical inward currents. In conclusion, this study provides evidence for the involvement of the voltage‐sensing domain of TRPM3 in the formation of an alternative ion permeation pathway. Abstract: Transient receptor potential (TRP) channels are cationic channels involved in a broad array of functions, including homeostasis, motility and sensory functions. TRP channel subunits consist of six transmembrane segments (S1–S6), and form tetrameric channels with a central pore formed by the region encompassing S5 and S6. Recently, evidence was provided for the existence of an alternative ion permeation pathway in TRPM3, which allows large inward currents upon hyperpolarization independently of the central pore. However, very little knowledge is available concerning the localization of this alternative pathway in the native TRPM3 channel protein. Guided by sequence homology with Shaker K+ channels, in which mutations in S4 can create an analogous ‘omega’ pore, we performed site‐directed mutagenesis studies and patch clamp experiments to identify amino acid residues involved in the formation of the non‐canonical pore in TRPM3. Based on our results, we pinpoint four residues in S4 (W982, R985, D988 and G991) as crucial determinants of the properties of the alternative ion permeation pathway. [ABSTRACT FROM AUTHOR]

The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic. TRPM2 has recently emerged as a likely candidate for the detector of non-noxious warmth, as it is expressed in sensory neurons, and mice show deficits in the detection of warmth when TRPM2 is genetically deleted. TRPM2 is a chanzyme, containing a thermally activated TRP ion channel domain attached to a C-terminal motif, derived from a mitochondrial ADP ribose pyrophosphatase, that confers on the channel sensitivity to ADP ribose and reactive oxygen species such as hydrogen peroxide. Several open questions remain. Male mammals prefer cooler environments than female, but the molecular basis of this sex difference is unknown. TRPM2 plays a role in regulating body temperature, but are other warmth-detecting mechanisms also involved? TRPM2 is expressed in autonomic neurons, but does it confer a sensory function in addition to the well-known motor functions of autonomic neurons? TRPM2 is thought to play important roles in the immune system, in pain and in insulin secretion, but the mechanisms are unclear. TRPM2 has to date received less attention than many other members of the TRP family but is rapidly assuming importance both in normal physiology and as a key target in disease pathology. [ABSTRACT FROM AUTHOR]

Eugenol is contained in several plants including clove and is used as an analgesic drug. In the peripheral and central nervous systems, this compound modulates neuronal activity through action on voltage-gated ionic channels and/or transient receptor potential channels. However, it is unknown whether eugenol exerts any effects on the respiratory center neurons in the medulla. We examined the effects of eugenol on respiratory rhythm generation in the brainstem-spinal cord preparation from newborn rat (P0-P3). The preparations were superfused by artificial cerebrospinal fluid at 25-26 °C, and inspiratory C4 ventral root activity was monitored. Membrane potentials of respiratory neurons were recorded in the parafacial region of the rostral ventrolateral medulla. Bath application of eugenol (0.5-1 mM) decreased respiratory rhythm accompanied by strong inhibition of the burst activity of pre-inspiratory neurons. After washout, respiratory rhythm partly recovered, but the inspiratory burst duration was extremely shortened, and this continued for more than 60 min after washout. The shortening of C4 inspiratory burst by eugenol was not reversed by capsazepine (TRPV1 antagonist) or HC-030031 (TRPA1 antagonist), whereas the depression was partially blocked by GABA antagonist bicuculline and glycine antagonist strychnine or GABA antagonist phaclofen. A spike train of action potentials in respiratory neurons induced by depolarizing current pulse was depressed by application of eugenol. Eugenol decreased the negative slope conductance of pre-inspiratory neurons, suggesting blockade of persistent Na current. These results suggest that changes in both membrane excitability and synaptic connections are involved in the shortening of respiratory neuron bursts by eugenol. [ABSTRACT FROM AUTHOR]

Key message: The trichome-related protein (TRP) is a novel transcription factor (TF) that negatively regulates trichome initiation-related TFs through gibberellin (GA) signaling.Abstract: Trichomes, which are outgrowths of leaf epidermal cells, provide the plant with a first line of defense against damage from herbivores and reduce transpiration. The initiation and development of trichomes are regulated by a network of positively or negatively regulating transcription factors (TFs). However, little information is currently available on transcriptional regulation related to trichome formation. Here, we report a novel TF Trichome-Related Protein (TRP) that was observed to negatively regulate the trichome initiation-related TFs through gibberellic acid (GA) signaling. ProTRP:GUS revealed that TRP was only expressed in the trichome. The TRP loss-of-function mutant (trp) had an increased number of trichomes on the flower, cauline leaves, and main inflorescence stems compared to the wild-type. In contrast, TRP overexpression lines (TRP-Ox) exhibited a decreased number of trichomes on cauline leaves and main inflorescence stem following treatment with exogenous GA. Moreover, the expressions of trichome initiation regulators (GIS, GIS2, ZFP8, GL1, and GL3) increased in trp plants but decreased in TRP-Ox lines after GA treatment. TRP was observed to physically interact with ZFP5, a C2H2 TF that controls trichome cell development through GA signaling, both in vivo and in vitro. Based on these results, we suggest that TRP functions upstream of the trichome initiation regulators and represses the binding of ZFP5 to the ZFP8 promoter. [ABSTRACT FROM AUTHOR]

· Plasma samples from patients with schizophrenia spectrum disorder were studied at three time points over a 5-year period. · Strongest changes in the kynurenine pathway were seen in antipsychotic-naïve patients. · There was a trend of inhibited KAT-II-driven events compared to KMO-related events. · Changes in the kynurenine pathway were associated with obesity and metabolic syndrome. The aim of this study was to evaluate how schizophrenia spectrum disorders (SSD) and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum levels of tryptophan (Trp) metabolites. A total of 112 adults (54 first-episode psychosis [FEP] patients and 58 control subjects [CSs]) participated in the study. The investigated changes in the metabolite levels appeared against a background of persistent increase in BMI and waist circumference among the patients. Regarding the kynurenine (KYN) pathway, the strongest changes were seen in AP-naïve FEP patients. Trp, KYN, kynurenic acid (KYNA), and anthranilic acid (ANT) levels were significantly reduced in blood samples from patients in the early stage of the disease. Furthermore, 3-OH-kynurenine (3-HK) and quinolinic acid (QUIN) levels were somewhat lower in these patients. Most of these changes in the KYN pathway became weaker with AP treatment. The levels of serotonin and its metabolite 5-HIAA tended to be higher at 5.1 years in patients showing the relation of elevated serotonin turnover to increased BMI and waist circumference. The similar trend was evident for the ratio between xanthurenic acid (XA) and KYNA with strong link to the elevated BMI. Altogether, the present study supports the role of Trp-metabolites in the development of obesity and metabolic syndrome in SSD patients. [Display omitted] Created with BioRender.com [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3R) are Ca2+ channels on the neuronal endoplasmic reticulum (ER) membrane. They are gated by IP3, produced upon external stimulation and activation of G protein-coupled receptors on the plasma membrane (PM). IP3-mediated Ca2+ release, and the resulting depletion of the ER store, triggers entry of extracellular Ca2+ by store-operated Ca2+ entry (SOCE). Mutations in IP3R attenuate SOCE. Compromised IP3R function and SOCE during pupal development of Drosophila leads to flight deficits and mimics suppression of neuronal activity during pupal or adult development. To understand the effect of compromised IP3R function on pupal neuronal calcium signaling, we examined the effects of mutations in the IP3R gene (itpr) on Ca2+ signals in cultured neurons derived from Drosophila pupae. We observed increased spontaneous Ca2+ influx across the PM of isolated pupal neurons with mutant IP3R and also a loss of SOCE. Both spontaneous Ca2+ influx and reduced SOCE were reversed by over-expression of dOrai and dSTIM, which encode the SOCE Ca2+ channel and the ER Ca2+-sensor that regulates it, respectively. Expression of voltage-gated Ca2+ channels (cac, Ca-α1D and Ca-αT) was significantly reduced in itpr mutant neurons. However, expression of trp mRNAs and transient receptor potential (TRP) protein were increased, suggesting that TRP channels might contribute to the increased spontaneous Ca2+ influx in neurons with mutant IP3R. Thus, IP3R/SOCE modulates spontaneous Ca2+ influx and expression of PM Ca2+ channels in Drosophila pupal neurons. Spontaneous Ca2+ influx compensates for the loss of SOCE in Drosophilaitpr mutant neurons.

ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.

Migraine is the second-most disabling disease worldwide, and the second most common neurological disorder. Attacks can last many hours or days, and consist of multiple symptoms including headache, nausea, vomiting, hypersensitivity to stimuli such as light and sound, and in some cases, an aura is present. Mechanisms contributing to migraine are still poorly understood. However, transient receptor potential (TRP) channels have been repeatedly linked to the disorder, including TRPV1, TRPV4, TRPM8, and TRPA1, based on their activation by pathological stimuli related to attacks, or their modulation by drugs/natural products known to be efficacious for migraine. This review will provide a brief overview of migraine, including current therapeutics and the link to calcitonin gene-related peptide (CGRP), a neuropeptide strongly implicated in migraine pathophysiology. Discussion will then focus on recent developments in preclinical and clinical studies that implicate TRP channels in migraine pathophysiology or in the efficacy of therapeutics. Given the use of onabotulinum toxin A (BoNTA) to treat chronic migraine, and its poorly understood mechanism, this review will also cover possible contributions of TRP channels to BoNTA efficacy. Discussion will conclude with remaining questions that require future work to more fully evaluate TRP channels as novel therapeutic targets for migraine.

Background: Nonea micrantha Boiss. & Reut. being an unexplored member of Boraginaceae was investigated for GC/MS analysis, acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and antioxidant activities in an attempt to find its effectiveness in neurological disorders. Methods: The AChE and BChE inhibitory activities of crude methanolic extract (Nm.Cr), subsequent fractions; n-hexane (Nm.Hex), chloroform (Nm.Cf), ethyl acetate (Nm.EtAc), aqueous (Nm.Aq) and crude saponins (Nm.Sp) from N. micrantha were conducted using Ellman's assay. The antioxidant activity of the plant samples using DPPH and ABTS free radical scavenging potential following quantitative spectrophotometric and qualitative TLC method were also studied. Moreover the total reducing power (TRP) of all the samples was also figured out. Results: The GC/Ms analysis confirmed that the plant is rich in bioactive molecules. Among different fractions, Nm.Hex, Nm.EtAc and Nm.Cf exhibited highest AChE inhibitory activities causing 75.51 ± 0.73, 68.54 ± 0.59 and 63.48 ± 0.59% enzyme inhibition respectively and IC50 of 44, 100 and 144 #181;g/mL respectively. In BChE inhibiton assay, Nm.Aq, Nm.Sp and Nm.Cr showed highest activity causing 83.49 ± 0.27, 81.49 ± 0.89 and 75.31 ± 0.56% enzyme inhibition with IC50 of 90, 110 and 44 #181;g/mL respectively. In DPPH assay, Nm.Aq, Nm.Cf, Nm.Hex and Nm.Cr were most potent exhibiting IC50 values of 3, 5, 93 and 120 #181;g/ml respectively. In ABTS assay Nm.EtAc, Nm.Aq, Nm.Sp and Nm.Cr showed IC50 values of 60, 95, 100 and 150 #181;g/mL respectively. Likewise ABTS inhibition was most prominent for Nm.Sp, Nm.EtAc and Nm.Aq causing 78.26 ± 0.49, 67.67 ± 0.73 and 63.58 ± 0.45% inhibition respectively at 1 mg/mL. These results were further confirmed by qualitative screening using DPPH and ABTS staining. Conclusions: Our anticholinesterase and antioxidant results signify the N. micrantha as a potential source of natural bioactive compounds. Moreover isolation of natural bioactive compounds from this plant may lead to novel drug candidates against neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Aim Ethanol is one of the most widely used recreational drugs in the world. At high concentrations, it can induce carotid artery vasoconstriction. Hyperthermia potentiates its effects resulting in carotid artery vasoconstriction at any concentration. The aim of this study is to investigate the interaction between ethanol and heating and to understand the underlying mechanisms leading to their synergistic effect. Materials and methods Isometric tension of rabbit carotid artery ring segments suspended in organ baths filled with Krebs solution was recorded. Different concentrations of ethanol were examined at 37 °C and during temperature elevation to39–43 °C. Capsaicin and capsazepine were used to examine the mechanism of action of ethanol. Key findings Ethanol induced contraction at 37 °C when the concentration reached 100 mM. Contraction was observed at any concentration at higher temperatures. Ethanol potentiated heat-induced contraction. Capsaicin, the vanilloid receptor subtype1 (TRPV1) agonist, potentiated the vasoconstriction due to heating. While capsazepine, TRPV1 antagonist, abolished the effect of ethanol and its potentiation of heating-induced contraction, but it did not abolish the heating effect. Significance Ethanol's mechanism of action and its effect on heating induced-vasoconstriction of the carotid artery is being mediated by TRPV1. The combination of ethanol and hyperthermia can lead to a synergistic effect on carotid vasoconstriction. This effect may induce brain damage and heat stroke. Development of new drugs act as TRPV1 antagonist can be used to prevent these fatal effects. [ABSTRACT FROM AUTHOR]

The obesity epidemic has turn into a major health threat worldwide and extensively responsible for the increased incidence of many diseases such as diabetes, cardiovascular disease and certain types of cancer. Excessive food intake along with the insufficient physical exercise is the basic impetus for this development. The aim of the present study is to evaluate the serum levels of leptin, zinc and tryptophan (TRP) in obese and non-obese subjects, which play major role in obesity. With the verbal and written consent eighty men were identified from the various areas of Karachi, Pakistan. The socio-demographic data including; age, body mass index (BMI), education and residence, of participants was collected. After providing informed consent, fasting blood samples were taken and serum was collected. The serum concentration of leptin, zinc and TRP were analyzed by ELISA (Enzyme-linked immunosorbent assay), FAAS (Flame atomic absorption spectrophotometer) and HPLC (High performance liquid chromatography) respectively. Results showed that levels of leptin were increased in obese than non-obese subjects significantly. On the other hand levels of zinc and TRP were significantly decreased in obese than non-obese subjects. Furthermore, there was a positive correlation found among leptin, zinc and TRP with obesity. Based on these facts the involvement of leptin, zinc and TRP with obesity will be discussed. [ABSTRACT FROM AUTHOR]

Membrane protein trafficking occurs throughout the lifetime of neurons and includes the initial protein synthesis and anterograde transport to the plasma membrane as well as internalization, degradation, and recycling of plasma membrane proteins. Defects in protein trafficking can result in neuronal degeneration and underlie blinding diseases such as retinitis pigmentosa as well as other neuronal disorders. Drosophila photoreceptor cells have emerged as a model system for identifying the components and mechanisms involved in membrane protein trafficking in neurons. Here we summarize the current knowledge about trafficking of three Drosophila phototransduction proteins, the visual pigment rhodopsin and the two light-activated ion channels TRP (transient receptor potential) and TRPL (TRP-like). Despite some common requirements shared by rhodopsin and TRP, details in the trafficking of these proteins differ considerably, suggesting the existence of several trafficking pathways for these photoreceptor proteins. [ABSTRACT FROM AUTHOR]

Tight control of basal cytosolic Ca concentration is essential for cell survival and to fine-tune Ca-dependent cell functions. A way to control this basal cytosolic Ca concentration is to regulate membrane Ca channels including store-operated Ca channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca channels contributes to Ca entry and the transient increase in cytosolic Ca concentration involved in intracellular signaling. However, in various experimental conditions, Ca entry and/or Ca currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca channels are already open/activated in basal condition, contributing therefore to constitutive Ca entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities. [ABSTRACT FROM AUTHOR]

Diseases of ruminant's stomach cause huge economic losses. Therefore, the present study was carried out to evaluate various ruminoreticular disorders and their effects on hematology and biochemical changes in blood and ruminal fluid as well as their effects on the ruminal protozoal activity and population in cattle. A total number of 46 cattle of both sexes (31 diseased cattle and 15 healthy control one) were included in the study. Cases were admitted at Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Assuit University, Assuit, Egypt during the period between July 2015 and November 2016. These animals were subjected to thorough clinical, ferroscopic, radiographical examination surgical exploration and laboratory investigation and divided into: TRP (n=7), vagus indigestion (n=5), impaction (n=5), free gas tympany (n=9) and frothy tympany (n=5). The results of this study showed that cases of TRP were suffered from obvious signs of pain, jugular pulsation in some animals. Ferroscopic examination was positive and Xrays showed presence of metal foreign objects. Hematological analysis showed significant decrease (P<0.01) in TRBCs count and Hb concentration and significant increase (P<0.01) in TWBCs and neutrophils counts. Serum biochemical analysis showed significant increase in total protein (P<0.01), globulin (P<0.05), and urea (P<0.05) concentration while there was significant decrease in the concentration of albumin, calcium (P<0.01), inorganic phosphorus (P<0.05), sodium (P<0.05) and zinc (P<0.01). Analysis of ruminal juice showed a dramatic decrease (P<0.01) in the activity and total number of protozoa, potassium, sodium and inorganic phosphorus concentrations. Animals with vagus indigestion showed characteristic abdomen distension (L-shape). Metal detector was negative in 2 animals and positive in 3 which were confirmed by X-rays. Hematological analysis showed significant decrease (P<0.01) in hemoglobin concentration with significant increase (P<0.01) in TWBCs, neutrophils and eosinophils counts. Serum biochemical analysis showed a significant increase (P<0.01) in the concentration of total protein globulin and urea and the activities of ALP, GGT with significant decrease in albumin (P<0.01) chloride (P<0.01) and inorganic phosphorus (P<0.05). Ruminal fluid analysis showed sharp decline in number and movement of protozoa and highly significant increase in chloride (P<0.01) and calcium (P<0.05) and significant decrease ((P<0.01) inorganic phosphorus concentrations. Animals with Impaction showed ruminal atony and slight decrease in body temperature. Hematological analysis revealed highly significant increase (P<0.01) in TWBCs, neutrophils counts and significant increase (P<0.05) monocytes count. Serum biochemical analysis showed significant increase (P<0.05) in urea, lactate (P<0.01) and sodium (P<0.05) while there were significant decrease (P<0.01) in potassium and inorganic phosphorus. Analysis of ruminal fluid showed highly significant decrease (P<0.01) in number and motility of protozoa, sodium, calcium and significant decrease (P<0.05) in potassium, and highly significant increase (P<0.01) in lactate concentration. Cases with free gas tympany were characterized by severe abdominal distention, anorexia, rapid heart rate and decrease rumen motility. Ferrosopic examination was negative in 6 animals and false positive in 3 animals which is confirmed by using X-rays. Hematological analysis revealed highly significant increase (P<0.01) TWBCs, neutrophil and significant increase (P<0.05) in eosinophil counts. Serum biochemical analysis showed significant increase in the concentration of globulin (P<0.05), urea (P<0.01) and sodium (P<0.05), and in the activities of ALP, GGT (P<0.01). Rumen fluid analysis showed highly significant decrease (P<0.01) in the total number and activity of ruminal protozoa and sodium and significant decrease (P<0.05) in ruminal potassium. Frothy tympany was characterized by severe abdominal distention and ruminalatony. Examined cases of frothy tympany were negative by metal detector and X-ray. Hematological analysis showed highly significant increase (P<0.01) in neutrophils count. Serum biochemical analysis showed highly significant increase (P<0.01) in the concentration of globulin and activities of ALP, GGT and significant increases (P<0.05) in serum urea and sodium (P<0.05). Rumen fluid analysis showed sharp decrease in the number and motility of protozoa. Ruminal biochemical analysis showed significant decrease (P<0.01) in sodium, potassium, inorganic phosphorus and calcium levels. In conclusion, diagnosis of ruminoreticular disorders depends collectively on history, clinical and ferroscopic examination. Radiographic examination is an important tool for differential diagnosis between traumatic and non-traumatic ruminoreticular disorders. Hematological and biochemical examination of serum and ruminal juice were of additional values in discriminating between various ruminoreticular disorders in cattle. [ABSTRACT FROM AUTHOR]

Propaganda and journalism both are two sides of the coin. Where propaganda is to provide more and more biased information about any institution, political party, personality and organization. At the same time, the principle of journalism is to serve the readers with truth baseline incident with news point of view. The media is being shaped event, incidents in propaganda and many times not in form of news they adopting this trend. Ram Rahim episode running in the present in form of propaganda, Nira Radia Case, Jammu and Kashmir issue, Students' movement in BHU, Triple Talaq, Yoga on Yoga Day, Killing of Hindus in Myanmar, Attack on Hotel Taj and Sansad Bhawan, Kedarnath Tragedy and many other news printed in print media and broadcasted in electronic media in propagate form. We can quote such examples for small and big level of propaganda, negative and positive propaganda done by print and electronic media. These news reports shows less news but propagate more and sometime more news and less propagate. Because in all these examples we can see electronic media broadcasted not only whole day but also continually one week, 15 days and one month. In this way, if reports are propagated, it also has negative effects on public opinion. In this research paper we will try to analysis it and we will also discuss about, if media do not serve the news in the way of propaganda, then it will probably be better if kept it in news form. Secondly print and electronic media also publish news of politicians, political parties as news is less but they propagate its more, which also has a profound effect on public opinion. Many times promotions of news in form of propaganda and it takes the form of sensation journalism. Through the propaganda the profession of journalism and the nature of journalism seems and has been growing in form of profession and seems very less as a mission. [ABSTRACT FROM AUTHOR]

Tunisian rock phosphate (TRP) extracted from the region of Gafsa is one of the most promising rock phosphates for soil fertilization. Its appropriate use as a source of phosphate nutrition can substitute chemical fertilizers for sustainable agriculture. The main objective of this study is to investigate the impact of P fertilizers on soil bacterial communities in the rhizosphere of bean ( Phaseolus vulgaris ). Application of chemical triple superphosphate (TSP) or TRP at similar P rates induced a significant increase in alkaline phosphatase and fluorescein diacetate hydrolysis activities. T-RFLP analysis of 16S rDNA revealed that P fertilization affected soil bacterial richness. Application of TRP at the same P rate as TSP was characterized by the stimulation of Actinobacteria both in the rhizosphere and in the uncultivated soil. Some of these Actinobacteria are known by their ability to produce organic acids thus promoting the dissolution of calcium and phosphore. Another important feature was the stimulation of ‘mycorrhiza helper bacteria’ like Comamonadaceae, Bradyrhizobacteriaceae and Oxalobacteraceae and other plant growth promoting bacteria such as Enterobacteriaceae and Pseudomonodaceae. These bacteria may contribute to the solubilization of phosphate through the production of organic acids (i.e., citric acid) and phytohormones (i.e., indol acetic acid) that stimulate plant root development and help P uptake by increasing the absorptive surface area. However, many putative plant growth promoting bacteria (mainly Sphingomonadaceae and Rhizobiaceae) were found to be inhibited by the chemical TSP fertilizer. [ABSTRACT FROM AUTHOR]

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies. [ABSTRACT FROM AUTHOR]

Protein-based particles are very promising colloidal systems for protection and controlled release applications in the food, cosmetics and pharmaceutical sector. One technique to produce these protein colloidal particles is liquid antisolvent precipitation (LAS). Despite the simplicity and versatility of LAS, not much is known about the protein conformational changes and interactions that are at the basis of the particle formation process. In this study, steady state fluorescence experiments using intrinsic fluorophores were evaluated as a tool to unravel the dynamics of the protein nanoparticle formation. Colloidal whey protein isolate and gliadin particles were produced by LAS. Changes in particle diameter (distribution), polydispersity index and photophysical properties of intrinsic fluorophores were monitored as a function of antisolvent concentration. By combining dynamic light scattering with photophysical data, a model of the changes occurring during particle formation and disintegration could be proposed. The results suggest that particle formation and disintegration are fully reversible processes during which the main changes in protein conformation (around the fluorescent probes) occur at the same antisolvent concentrations. In principle, steady state fluorescence measurements using intrinsic probes can indeed be used to effectively report on (part of the) conformational changes for both protein systems under study. [ABSTRACT FROM AUTHOR]

In the past few decades, the so-feared botulinum toxin has conversely acquired the role of a ever more versatile therapeutic substance, used in an increasing number of pathological situations, including chronic headache and more precisely in the prophylaxis of chronic migraine. The medical use of botulinum toxin allowed to better understand its multiple mechanisms of action. Investigations about the pathophysiology of primary and secondary headaches has shown a series of common biological elements that frequently are also targets of the action of botulinum toxin. These increasing evidences allowed to identify some biochemical, neurophysiological and radiological markers that may be useful in the individuation of patients which probably will respond to the treatment with Onabotulinum toxin-A among chronic migraineurs. These predictors include CGRP plasmatic levels, specific laser-evoked potential responses, peculiar brain MRI and fMRI and characteristic clinical manifestations. Unfortunately, at now, these predictors are still not available for the clinical practice. Furthermore, the better knowledge about biology of headaches and regarding botulinum toxin activities may also help in directing investigations on the possible use of Onabotulinum toxin-A in other headaches different from migraine. This review tries to show in detail these biological mechanisms and their implication in selecting patients eligible for the treatment with Onabotulinum toxin-A. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3R) are Ca2+ channels on the neuronal endoplasmic reticulum (ER) membrane. They are gated by IP3, produced upon external stimulation and activation of G protein-coupled receptors on the plasma membrane (PM). IP3-mediated Ca2+ release, and the resulting depletion of the ER store, triggers entry of extracellular Ca2+ by store-operated Ca2+ entry (SOCE). Mutations in IP3R attenuate SOCE. Compromised IP3R function and SOCE during pupal development of Drosophila leads to flight deficits and mimics suppression of neuronal activity during pupal or adult development. To understand the effect of compromised IP3R function on pupal neuronal calcium signaling, we examined the effects of mutations in the IP3R gene (itpr) on Ca2+ signals in cultured neurons derived from Drosophila pupae. We observed increased spontaneous Ca2+influx across the PM of isolated pupal neurons with mutant IP3R and also a loss of SOCE. Both spontaneous Ca2+ influx and reduced SOCE were reversed by over-expression of dOrai and dSTIM, which encode the SOCE Ca2+ channel and the ER Ca2+-sensor that regulates it, respectively. Expression of voltage-gated Ca2+ channels (cac, Ca-αD and Ca-αT) was significantly reduced in itpr mutant neurons. However, expression of trp mRNAs and transient receptor potential (TRP) protein were increased, suggesting that TRP channels might contribute to the increased spontaneous Ca2+ influx in neurons with mutant IP3R. Thus, IP3R/SOCE modulates spontaneous Ca2+ influx and expression of PM Ca2+ channels in Drosophila pupal neurons. Spontaneous Ca2+ influx compensates for the loss of SOCE in Drosophila itpr mutant neurons. [ABSTRACT FROM AUTHOR]

Obesity is a worldwide epidemic leading to decreased quality of life, higher medical expenses and significant morbidity. Enhancing energy expenditure and substrate utilization in adipose tissues through dietary constituents and polypharmacological approaches is gaining importance for the prevention and therapeutics of obesity. An important factor in this regard is Transient Receptor Potential (TRP) channel modulation and resultant activation of "brite" phenotype. Various dietary TRP channel agonists like capsaicin (TRPV1), cinnamaldehyde (TRPA1), and menthol (TRPM8) have shown anti-obesity effects, individually and in combination. We aimed to determine the therapeutic potential of such combination of sub-effective doses of these agents against diet-induced obesity, and explore the involved cellular processes. The combination of sub-effective doses of capsaicin, cinnamaldehyde and menthol induced "brite" phenotype in differentiating 3T3-L1 cells and subcutaneous white adipose tissue of HFD-fed obese mice. The intervention prevented adipose tissue hypertrophy and weight gain, enhanced the thermogenic potential, mitochondrial biogenesis and overall activation of brown adipose tissue. These changes observed in vitro as well as in vivo, were linked to increased phosphorylation of kinases, AMPK and ERK. In the liver, the combination treatment enhanced insulin sensitivity, improved gluconeogenic potential and lipolysis, prevented fatty acid accumulation and enhanced glucose utilization. We report on the discovery of therapeutic potential of TRP-based dietary triagonist combination against HFD-induced abnormalities in metabolic tissues. Our findings indicate that a common central mechanism may affect multiple peripheral tissues. This study opens up avenues of development of therapeutic functional foods for obesity. In 3T3L1 cells the triagonist combination reduced lipid accumulation and adipocyte differentiation from preadipocytes. This also promotes effective glucose utilization along with enhanced thermogenic activities mediated through intracellular calcium uptake leading to phosphorylation on AMPK and enhanced UCP-1 expression. This possibly could be due to increased mitochondrial biogenesis and its activities. In in-vivo settings as a therapeutic approach in HFD-induced mice it promotes browning of white adipose tissue and enhanced the activity of brown adipose tissue by factors modulating the lipid metabolism such as PPAR-γ, PGC1α, PRDM16, SIRT-1 which mechanistically upregulated upon increased phosphorylation of ERK and AMPK in mitochondria. The mitochondrial thermogenic capacity by increased UCP-1 protein expression by CB treatment also affects the overall energy expenditure capacity. In liver this promotes the glucose utilization and effective handling of glucose by enhanced gluconeogenesis and lipolysis for ectopic fat deposition. This also promotes the insulin sensitivity by modifying the disease progression factors. [Display omitted] • Dietary components based polypharmacological approaches gaining interest to counter obesity and associated complications. • Transient Receptor potential (TRP) channels agonists and their combinations from food origin could provide novel intervention strategies against obesity. [ABSTRACT FROM AUTHOR]

Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia spp. affecting over 120 million people. Heavy infections can lead to elephantiasis, which has serious effects on individuals' lives. Although current anthelmintics are effective at killing microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open transient receptor potential (TRP) channels in the muscles of adult female Brugia malayi, leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on Brugia, inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trial for the treatment of river blindness. Here, we have studied the effects of diethylcarbamazine on single Brugia muscle cells by measuring the change in Ca 2+ fluorescence in the muscle using Ca 2+ -imaging techniques. Diethylcarbamazine interacts with the transient receptor potential channel, C classification (TRPC) ortholog receptor TRP-2 to promote Ca 2+ entry into the Brugia muscle cells, which can activate Slopoke (SLO-1) Ca 2+ -activated K + channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca 2+ signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca 2+ entry that is increased by emodepside activation of SLO-1 K + channels., Competing Interests: The authors declare no conflict of interest.

The kynurenine pathway (KP) of tryptophan has been implicated in the pathogenesis of schizophrenia and its interaction with the immune system has been suggested to play a role. In this study, 28 schizophrenia patients and 25 healthy controls were recruited and divided into different inflammatory subgroups using a two-step recursive clustering analysis. Cytokine gene expression and plasma KP metabolites were measured before, during and after treatment. Our findings indicated that schizophrenia patients had lower levels of Tryptophan (TRP), N-formylkynurenine (NFK), xanthinic acid (XA), quinolinic acid (QA), kynurenic acid (KYNA), KYNA/KYN and QA/KYNA, but higher levels of IL-18 mRNA, KYN/TRP compared to healthy controls (all p < 0.05). After electroconvulsive therapy (ECT), patients with low inflammation achieved better clinical improvement (PANSS scores) compared to those with high inflammation (F = 5.672, P = 0.025), especially in negative symptoms (F = 6.382, P = 0.018, η 2  = 0.197). While IL-18 mRNA (F = 32.910, P < 0.0001) was significantly decreased following ECT, the KYN/TRP (F = 3.455, p = 0.047) and KYNA/TRP (F = 4.264, P = 0.026) only significantly decreased in patients with low inflammation. Correlation analyses revealed that baseline IL-18 gene expression significantly correlated with pre- (r = 0.537, p = 0.008) and post-KYNA/TRP (r = 0.443, p = 0.034), post-KYN/TRP (r = 0.510, p = 0.013), and post-negative symptoms (r = 0.525, p = 0.010). Moreover, baseline TRP (r = -0.438, p = 0.037) and XA (r = -0.516, p = 0.012) were negatively correlated with baseline PANSS, while post-KYN (r = -0.475, p = 0.022), 2-AA (r = -0.447, p = 0.032) and KYN/TRP (r = -0.566, p = 0.005) were negatively correlated with Montreal Cognitive Assessment (MoCA) following ECT. Overall, these findings suggested that the association between inflammation and kynurenine pathway plays an essential role in mechanism of ECT for schizophrenia and that the regulation of ECT on KP is influenced by inflammatory characteristics, which may relate to clinical efficacy in schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Environmental co-exposure to allergen and traffic-related air pollution is common globally and contributes to the exacerbation of respiratory diseases. Individual responses to environmental insults remain variable due to gene-environment interactions., Objective: This study examined whether single nucleotide polymorphisms (SNPs) in lung cell surface receptor genes modifies lung function change and immune cell recruitment in allergen-sensitized individuals exposed to diesel exhaust (DE) and allergen., Methods: In this randomized, double-blinded, four-arm, crossover study, 13 allergen-sensitized participants underwent allergen inhalation challenge following a 2-hour exposure to DE, particle-depleted diesel exhaust (PDDE) or filtered air (FA). Lung function tests and bronchoscopic sample collection were performed up to 48 h after exposures. Transient receptor potential channel (TRPA1 and TRPV1) and toll-like receptor (TLR2 and TLR4) risk alleles were used to construct an unweighted genetic risk score (GRS). Exposure-by-GRS interactions were tested using mixed-effects models., Results: In participants with high GRS, allergen exposure was associated with an increase in airway hyperresponsiveness (AHR) when co-exposed to PDDE (p = 0.03) but not FA or DE. FA and PDDE also were associated with a relative increase in macrophages and decrease in lymphocytes in bronchoalveolar lavage., Conclusions: TRPs and TLRs variants are associated with increased AHR and altered immune cellularity in allergen-exposed individuals. This effect is blunted by DE exposure, suggesting greater influence of unmeasured gene variants as primary meditators of a particulate-rich co-exposure., Trial Registration: The study was registered with ClinicalTrials.gov on December 20, 2013 (NCT02017431)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mechanosensitive ion channels comprise a broad group of proteins that sense mechanical extracellular and intracellular changes, translating them into cation influx to adapt and respond to these physical cues. All cells in the organism are mechanosensitive, and these physical cues have proven to have an important role in regulating proliferation, cell fate and differentiation, migration and cellular stress, among other processes. Indeed, the mechanical properties of the extracellular matrix in cancer change drastically due to high cell proliferation and modification of extracellular protein secretion, suggesting an important contribution to tumor cell regulation. In this review, we describe the physiological significance of mechanosensitive ion channels, emphasizing their role in cancer and immunity, and providing compelling proof of the importance of continuing to explore their potential as new therapeutic targets in cancer research.

The urothelium, which covers the inner surface of the bladder, is continuously exposed to a complex physical environment where it is stimulated by, and responds to, a wide range of mechanical cues. Mechanically activated ion channels endow the urothelium with functioning in the conversion of mechanical stimuli into biochemical events that influence the surface of the urothelium itself as well as suburothelial tissues, including afferent nerve fibres, interstitial cells of Cajal and detrusor smooth muscle cells, to ensure normal urinary function during the cycle of filling and voiding. However, under prolonged and abnormal loading conditions, the urothelial sensory system can become maladaptive, leading to the development of bladder dysfunction. In this review, we summarize developments in the understanding of urothelial mechanotransduction from two perspectives: first, with regard to the functions of urothelial mechanotransduction, particularly stretch-mediated ATP signalling and the regulation of urothelial surface area; and secondly, with regard to the mechanoreceptors present in the urothelium, primarily transient receptor potential channels and mechanosensitive Piezo channels, and the potential pathophysiological role of these channels in the bladder. A more thorough understanding of urothelial mechanotransduction function may inspire the development of new therapeutic strategies for lower urinary tract diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Voltage-gated Ca2+ channels are involved in numerous physiological functions and various mechanisms finely tune their activity, including the Ca2+ ion itself. This is well exemplified by the Ca2+-dependent inactivation of L-type Ca2+ channels, whose alteration contributes to the dramatic disease Timothy Syndrome. For T-type Ca2+ channels, a long-held view is that they are not regulated by intracellular Ca2+. Here we challenge this notion by using dedicated electrophysiological protocols on both native and expressed T-type Ca2+ channels. We demonstrate that a rise in submembrane Ca2+ induces a large decrease in T-type current amplitude due to a hyperpolarizing shift in the steady-state inactivation. Activation of most representative Ca2+-permeable ionotropic receptors similarly regulate T-type current properties. Altogether, our data clearly establish that Ca2+ entry exerts a feedback control on T-type channel activity, by modulating the channel availability, a mechanism that critically links cellular properties of T-type Ca2+ channels to their physiological roles.