Sodium entry through endothelial store-operated calcium entry channels: regulation by Orai1

Lee

et al. 2017

Sci Rep

Odorants are non-nutrients. However, they exist abundantly in foods, wines, and teas, and thus can be ingested along with the other nutrients during a meal. Here, we have focused on the chemical-recognition ability of these ORs and hypothesized that the odorants ingested during a meal may play a physiological role by activating the gut-expressed ORs. Using a human-derived enteroendocrine L cell line, we discovered the geraniol- and citronellal-mediated stimulation of glucagon-like peptide-1 (GLP-1) secretion and elucidated the corresponding cellular downstream signaling pathways. The geraniol-stimulated GLP-1 secretion event in the enteroendocrine cell line was mediated by the olfactory-type G protein, the activation of adenylyl cyclase, increased intracellular cAMP levels, and extracellular calcium influx. TaqMan qPCR demonstrated that two ORs corresponding to geraniol and citronellal were expressed in the human enteroendocrine cell line and in mouse intestinal specimen. In a type 2 diabetes mellitus mouse model (db/db), oral administration of geraniol improved glucose homeostasis by increasing plasma GLP-1 and insulin levels. This insulinotropic action of geraniol was GLP-1 receptor-mediated, and also was glucose-dependent. This study demonstrates that odor compounds can be recognized by gut-expressed ORs during meal ingestion and therefore, participate in the glucose homeostasis by inducing the secretion of gut-peptides.

Section: Resultsmentioning

confidence: 99%

Activation of intestinal olfactory receptor stimulates glucagon-like peptide-1 secretion in enteroendocrine cells and attenuates hyperglycemia in type 2 diabetic mice

Lee

et al. 2017

Sci Rep

Journal Cellular Physiology

“…Once arrived in close apposition, that is, 10–20 nm, to the PM, Stim1 assemblies into spatially restricted clusters or puncta at level of which it binds to and gates at least two Ca 2+ ‐permeable channels, such as Orai1 and/or TRPC1 (Ong & Ambudkar, ; Prakriya & Lewis, ). This mode of Ca 2+ inflow has been termed store‐operated Ca 2+ entry (SOCE) and represents the major route for Ca 2+ influx in vascular endothelial cells (Abdullaev et al, ; Cioffi et al, ; Jho et al, ; Li et al, ; Sundivakkam et al, ; Xu, Cioffi, Alexeyev, Rich, & Stevens, ). We will not address here the complex discussion about the molecular details of the physical interaction between Stim1 and Orai1 and/or TRPC1, which has been exhaustively described elsewhere (Cioffi, Barry, & Stevens, ; Ong & Ambudkar, ; Prakriya & Lewis, ).…”

Section: Introductionmentioning

confidence: 99%

TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

Moccia

Lucariello

Guerra³

2017

Endothelial progenitor cells (EPCs) are a sub-population of bone marrow-derived mononuclear cells that are released in circulation to restore damaged endothelium during its physiological turnover or rescue blood perfusion after an ischemic insult. Additionally, they may be mobilized from perivascular niches located within larger arteries' wall in response to hypoxic conditions. For this reason, EPCs have been regarded as an effective tool to promote revascularization and functional recovery of ischemic hearts, but clinical application failed to exploit the full potential of patients-derived cells. Indeed, the frequency and biological activity of EPCs are compromised in aging individuals or in subjects suffering from severe cardiovascular risk factors. Rejuvenating the reparative phenotype of autologous EPCs through a gene transfer approach has, therefore, been put forward as an alternative approach to enhance their therapeutic potential in cardiovascular patients. An increase in intracellular Ca concentration constitutes a pivotal signal for the activation of the so-called endothelial colony forming cells (ECFCs), the only known truly endothelial EPC subset. Studies from our group showed that the Ca toolkit differs between peripheral blood- and umbilical cord blood (UCB)-derived ECFCs. In the present article, we first discuss how VEGF uses repetitive Ca spikes to regulate angiogenesis in ECFCs and outline how VEGF-induced intracellular Ca oscillations differ between the two ECFC subtypes. We then hypothesize about the possibility to rejuvenate the biological activity of autologous ECFCs by transfecting the cell with the Ca -permeable channel Transient Receptor Potential Canonical 3, which selectively drives the Ca response to VEGF in UCB-derived ECFCs.

“…Therefore, one could speculate that Orai1-mediated extracellular Ca 2+ entry triggers TRPC1 insertion into the plasma membrane, followed by STIM1dependent recruitment, as demonstrated in human salivary gland cells (Cheng et al, 2011). Alternately, it has been shown that the endothelial Orai1 may assemble and determine the Ca 2+selectivity of a heteromeric complex also involving TRPC1, TRPC4 and, possibly, TRPV4 (Brough et al, 2001;Cioffi et al, 2005;Ma et al, 2011a;Cioffi et al, 2012;Xu et al, 2015). Therefore, the controversial contribution of TRPC1 (and TRPC4) to VEGF-induced endothelial SOCE may reflect multiple factors, including cell source, cell passage, culture medium, substrate of adhesion, experimental protocols, detection methods and so on (Beech, 2012).…”

Section: General Mechanisms For Growth Factors-induced Intracellular mentioning

confidence: 98%

Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis

et al. 2020

Vasculogenesis, angiogenesis and arteriogenesis represent three crucial mechanisms involved in the formation and maintenance of the vascular network in embryonal and post-natal life. It has long been known that endothelial Ca 2+ signals are key players in vascular remodeling; indeed, multiple pro-angiogenic factors, including vascular endothelial growth factor, regulate endothelial cell fate through an increase in intracellular Ca 2+ concentration. Transient Receptor Potential (TRP) channel consist in a superfamily of non-selective cation channels that are widely expressed within vascular endothelial cells. In addition, TRP channels are present in the two main endothelial progenitor cell (EPC) populations, i.e., myeloid angiogenic cells (MACs) and endothelial colony forming cells (ECFCs). TRP channels are polymodal channels that can assemble in homo-and heteromeric complexes and may be sensitive to both pro-angiogenic cues and subtle changes in local microenvironment. These features render TRP channels the most versatile Ca 2+ entry pathway in vascular endothelial cells and in EPCs. Herein, we describe how endothelial TRP channels stimulate vascular remodeling by promoting angiogenesis, arteriogenesis and vasculogenesis through the integration of multiple environmental, e.g., extracellular growth factors and chemokines, and intracellular, e.g., reactive oxygen species, a decrease in Mg 2+ levels, or hypercholesterolemia, stimuli. In addition, we illustrate how endothelial TRP channels induce neovascularization in response to synthetic agonists and small molecule drugs. We focus the attention on TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPV1, TRPV4, TRPM2, TRPM4, TRPM7, TRPA1, that were shown to be involved in angiogenesis, arteriogenesis and vasculogenesis. Finally, we discuss the role of endothelial TRP channels in aberrant tumor vascularization by focusing on TRPC1, TRPC3, TRPV2, TRPV4, TRPM8, and TRPA1. These observations suggest that endothelial TRP channels represent potential therapeutic targets in multiple disorders featured by abnormal vascularization, including cancer, ischemic disorders, retinal degeneration and neurodegeneration.