Herbal Compounds and Toxins Modulating TRP Channels

Although the benefits are sometimes obvious, traditional or herbal medicine is regarded with skepticism, because the mechanism through which plant compounds exert their powers are largely elusive. Recent studies have shown however that many of these plant compounds interact with specific ion channels and thereby modulate the sensing mechanism of the human body. Especially members of the Transient Receptor Potential (TRP) channels have drawn large attention lately as the receptors for plant-derived compounds such as capsaicin and menthol. TRP channels constitute a large and diverse family of channel proteins that can serve as versatile sensors that allow individual cells and entire organisms to detect changes in their environment. For this family, a striking number of empirical views have turned into mechanism-based actions of natural compounds. In this review we will give an overview of herbal compounds and toxins, which modulate TRP channels

TRPM3 Is a Nociceptor Channel Involved in the Detection of Noxious Heat

SummaryTransient receptor potential melastatin-3 (TRPM3) is a broadly expressed Ca2+-permeable nonselective cation channel. Previous work has demonstrated robust activation of TRPM3 by the neuroactive steroid pregnenolone sulfate (PS), but its in vivo gating mechanisms and functions remained poorly understood. Here, we provide evidence that TRPM3 functions as a chemo- and thermosensor in the somatosensory system. TRPM3 is molecularly and functionally expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and mediates the aversive and nocifensive behavioral responses to PS. Moreover, we demonstrate that TRPM3 is steeply activated by heating and underlies heat sensitivity in a subset of sensory neurons. TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. These experiments reveal an unanticipated role for TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.This is the final version of the article. It was first available from the American Society for Clinical Investigation via http://dx.doi.org/10.1172/JCI8197

From cardiac cation channels to the molecular dissection of the transient receptor potential channel TRPM4

In 2006, we celebrate not only the milestone paper on the patch-clamp technique [14] but also the publication of the first single-channel measurements in cardiac cells revealing a Ca(2+)-activated, nonselective cation channel [6]. Considerable effort has been undertaken since this time to identify molecular candidates for this class of cation channels that can be found in a variety of tissues. Recent work has shown that this channel is very likely TRPM4, a member of the TRPM ion channel family. The current review links the epochal Colquhoun et al. paper to the detailed molecular knowledge and structure function aspects of this TRP channel. It will be shown that TRPM4 is a Ca(2+)- and voltage-activated channel, which is dramatically modulated by the phospholipid phosphatidyl inositol bisphosphate (PIP(2)) and belongs to the heat-activated thermoTRPs. A functional hallmark of TRPM4, as for several TRP channels, is a dramatic shift of its voltage dependence towards negative, physiologically meaningful potentials.status: publishe

On the putative role of transient receptor potential cation channels in asthma

The mammalian transient receptor potential (TRP) superfamily consists of 28 mammalian TRP cation channels, which can be subdivided into six main subfamilies: the TRPC ('Canonical'), TRPV ('Vanilloid'), TRPM ('Melastatin'), TRPP ('Polycystin'), TRPML ('Mucolipin') and the TRPA ('Ankyrin') groups. Increasing evidence has accumulated during the previous few years that links TRP channels to the cause of several diseases or to critically influence and/or determine their progress. This review focuses on the possible role of TRP channels in the aetiology of asthmatic lung disease.status: publishe

Targeting TRP Channels - Valuable Alternatives to Combat Pain, Lower Urinary Tract Disorders, and Type 2 Diabetes?

Transient receptor potential (TRP) channels are a family of functionally diverse and widely expressed cation channels involved in a variety of cell signaling and sensory pathways. Research in the last two decades has not only shed light on the physiological roles of the 28 mammalian TRP channels, but also revealed the involvement of specific TRP channels in a plethora of inherited and acquired human diseases. Considering the historical successes of other types of ion channels as therapeutic drug targets, small molecules that target specific TRP channels hold promise as treatments for a variety of human conditions. In recent research, important new findings have highlighted the central role of TRP channels in chronic pain, lower urinary tract disorders, and type 2 diabetes, conditions with an unmet medical need. Here, we discuss how these advances support the development of TRP-channel-based pharmacotherapies as valuable alternatives to the current mainstays of treatment.status: publishe

Vanilloid transient receptor potential cation channels: An overview

The mammalian branch of the Transient Receptor Potential ( TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC ('Canonical'), TRPV ('Vanilloid'), TRPM ('Melastatin'), TRPP ('Polycystin'), TRPML ('Mucolipin') and the TRPA ('Ankyrin') group. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing ( TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/ reabsorption in mammals ( TRPV5, TRPV6). In this review we summarize fundamental physiological properties of all TRPV members in the light of various cellular functions of these channels and their significance in the systemic context of the mammalian organism.status: publishe

Stevia Sweetener Enhances Pancreatic Beta-Cell Function by Potentiating TRPM5 Channel Activity

Steviol glycosides as stevioside and rebaudioside A are natural, non-caloric sweet-tasting organic molecules, present in the extracts of the scrub plant Stevia rebaudiana, which are widely used as sweeteners in consumer foods and beverages. TRPM5 is a Ca2+-activated cation channel expressed in pancreatic β-cells. We show potentiation of TRPM5 with stevioside, rebaudioside A and their aglycon steviol. In this way, there is an enhanced glucose-induced insulin secretion in a Trpm5-dependent manner. The daily consumption of stevioside prevents the development of high-fat-diet-induced diabetic hyperglycaemia in wild-type mice, but not in Trpm5−/− mice. In isolated human pancreatic islets, there is a stevioside-induced potentiation of the intracellular calcium dynamics. This is indicative for increased insulin secretion, as is observed with mice. These results elucidate a molecular mechanism of action of steviol glycosides and identify TRPM5 as a potential target to prevent and treat type 2 diabetes.status: publishe

A Thallium-Based Screening Procedure to Identify Molecules That Modulate the Activity of Ca2+-Activated Monovalent Cation-Selective Channels

TRPM5 functions as a calcium-activated monovalent cation-selective ion channel and is expressed in a variety of cell types. Dysfunction of this type of channel has been recently implied in cardiac arrhythmias, diabetes, and other pathologies. Therefore, a growing interest has emerged to develop the pharmacology of these ion channels. We optimized a screening assay based on the thallium flux through the TRPM5 channel and a fluorescent thallium dye as a probe for channel activity. We show that this assay is capable of identifying molecules that inhibit or potentiate calcium-activated monovalent cation-selective ion channels.status: publishe