ORCID Profile
0000-0003-3113-1671
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Publisher: Wiley
Date: 25-12-2022
DOI: 10.1113/JP282502
Abstract: Three Orai (Orai1, Orai2, and Orai3) and two stromal interaction molecule (STIM1 and STIM2) mammalian protein homologues constitute major components of the store‐operated Ca 2+ entry mechanism. When co‐expressed with STIM1, Orai1, Orai2 and Orai3 form highly selective Ca 2+ channels with properties of Ca 2+ release‐activated Ca 2+ (CRAC) channels. Despite the high level of homology between Orai proteins, CRAC channels formed by different Orai isoforms have distinctive properties, particularly with regards to Ca 2+ ‐dependent inactivation, inhibition otentiation by 2‐aminoethyl diphenylborinate and sensitivity to reactive oxygen species. This study characterises and compares the regulation of Orai1, Orai2‐ and Orai3‐mediated CRAC current ( I CRAC ) by intracellular pH (pH i ). Using whole‐cell patch cl ing of HEK293T cells heterologously expressing Orai and STIM1, we show that I CRAC formed by each Orai homologue has a unique sensitivity to changes in pH i . Orai1‐mediated I CRAC exhibits a strong dependence on pH i of both current litude and the kinetics of Ca 2+ ‐dependent inactivation. In contrast, Orai2 litude, but not kinetics, depends on pH i , whereas Orai3 shows no dependence on pH i at all. Investigation of different Orai1–Orai3 chimeras suggests that pH i dependence of Orai1 resides in both the N‐terminus and intracellular loop 2, and may also involve pH‐dependent interactions with STIM1. image It has been shown previously that Orai1/stromal interaction molecule 1 (STIM1)‐mediated Ca 2+ release‐activated Ca 2+ current ( I CRAC ) is inhibited by intracellular acidification and potentiated by intracellular alkalinisation. The present study reveals that CRAC channels formed by each of the Orai homologues Orai1, Orai2 and Orai3 has a unique sensitivity to changes in intracellular pH (pH i ). The litude of Orai2 current is affected by the changes in pH i similarly to the litude of Orai1. However, unlike Orai1, fast Ca 2+ ‐dependent inactivation of Orai2 is unaffected by acidic pH i . In contrast to both Orai1 and Orai2, Orai3 is not sensitive to pH i changes. Domain swapping between Orai1 and Orai3 identified the N‐terminus and intracellular loop 2 as the molecular structures responsible for Orai1 regulation by pH i . Reduction of I CRAC dependence on pH i seen in a STIM1‐independent Orai1 mutant suggested that some parts of STIM1 are also involved in I CRAC modulation by pH i .
Publisher: MDPI AG
Date: 21-08-2014
Publisher: Informa UK Limited
Date: 09-2022
DOI: 10.2147/DDDT.S380925
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.IJPHARM.2016.09.039
Abstract: In recent years G protein-coupled receptors (GPCRs) have emerged as crucial tumorigenic factors that drive aberrant cancer growth, metastasis and angiogenesis. Consequently, a number of GPCRs are strongly expressed in cancer derived cell lines and tissue s les. Therefore a rational anti-cancer strategy is the design of nano-medicines that specifically target GPCRs to bind and internalise cytotoxic drugs into cancer cells. Herein, we report the genetic engineering of a self-assembling nanoparticle based on elastin-like polypeptide (ELP), which has been fused with gastrin releasing peptide (GRP). These nanoparticles increased intracellular calcium concentrations when added to GRP receptor positive PC-3 prostate cancer cells, demonstrating specific receptor activation. Moreover, GRP-displaying fluorescent labelled nanoparticles showed specific cell-surface interaction with PC-3 prostate cancer cells and increased endocytic uptake. These nanoparticles therefore provide a targeted molecular carrier system for evaluating the delivery of cytotoxic drugs into cancer cells.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.BONE.2014.11.022
Abstract: Although bone pain caused by cancer chemotherapy is a well-recognized and significant problem, with approximately 1 in 10 childhood cancer patients being reported to experience isolated bone pain along with other skeletal complications, the underlying mechanisms are poorly understood and there is no specific treatment. In this study, effects of methotrexate (MTX) treatment on pain in the hind legs and the extent of sensory innervation of the tibial bone were examined through a 20-day time course in young rats after 5 daily 0.75 mg/kg MTX injections. MTX treatment increased von-Frey filament stimulation-induced mechanical allodynia and palpation nocifensive score in the tibia. MTX-treated rats showed trends in reduced loading (numbers of stands) on hind limbs after palpation, commencing early during treatment and 2 weeks after the end of treatment despite no signs of ongoing pain during normal locomotion. Immunohistochemical analyses showed an increase in innervation of calcitonin gene-related peptide (CGRP)-positive sensory nerve fibres in tibial periosteum on days preceding and overlapping with those rats with touch-evoked pain responses and the bone repair phase. These data suggest that methotrexate chemotherapy triggers touch-evoked pain involving enhanced sensory nerve innervation of the bone.
Publisher: Spandidos Publications
Date: 21-08-2020
Publisher: Elsevier BV
Date: 02-2021
No related grants have been discovered for Fiona Zhou.