Store-operated Ca2+ channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells

School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 06/2008; 1783(5):874-85. DOI: 10.1016/j.bbamcr.2008.02.011
Source: PubMed


This article is about resettled Afghan Hazaras in Australia, many of whom are currently undergoing a complex process of transition (from transience into a more stable position) for the first time in their lives. Despite their permanent residency status, we show how resettlement can
be a challenging transitional experience. For these new migrants, we argue that developing a sense of belonging during the transition period is a critical rite of passage in the context of their political and cultural identity. A study of forced migrants such as these, moving out of one transient
experience into another transitional period (albeit one that holds greater promise and permanence) poses a unique intellectual challenge. New understandings about the ongoing, unpredictable consequences of ‘transience’ for refugee communities is crucial as we discover what might
be necessary, as social support structures, to facilitate the process of transition into a distinctly new environment. The article is based on a doctoral ethnographic study of 30 resettled Afghan Hazara living in the region of Dandenong in Melbourne, Australia. Here, we include four of these
participants’ reflections of transition during different phases of their resettlement. These reflections were particularly revealing of the ways in which some migrants deal with change and acquire a sense of belonging to the community. Taking a historical view, and drawing on Bourdieu’s
notion of symbolic social capital to highlight themes in individual experiences of belonging, we show how some new migrants adjust and learn to ‘embody’ their place in the new country. Symbolic social capital illuminates how people access and use resources such as social networks
as tools of empowerment, reflecting how Hazara post-arrival experiences are tied to complex power relations in their everyday social interactions and in their life trajectories as people in transition. We learned that such tools can facilitate the formation of Hazara migrant identities and
are closely tied to their civic community participation, English language development, and orientation in, as well as comprehension of local cultural knowledge and place. This kind of theorization allows refugee, post-refugee and recent migrant narratives to be viewed not merely as static
expressions of loss, trauma or damage, but rather as individual experiences of survival, adaptation and upward mobility.

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Available from: Edoardo C Aromataris, Dec 12, 2013
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    • "The long-standing mystery of the molecular composition of CRAC channels has hampered the identification of specific inhibitors. Nevertheless a variety of compounds that strongly inhibit CRAC currents has been identified including divalent and trivalent cations such as La3+ and Gd3+, diverse imidazoles, 2-APB (2-aminoethoxydiphenylborate), capsaicin [2], NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid) [3–5], BTP2 (a bistrifluoromethyl-pyrazole derivative) [6–8], DES (diethylstilbestrol) [9], BEL (bromenol lactone) [10], bile acids [11] and ML-9 (1-(5-chloronaphthalene-1-sulfonyl)homopiperazine) [12]. La3+ and Gd3+ represent general inhibitors of Ca2+-selective influx pathways comprising voltage-dependent Ca2+, TRPV5/6 and also CRAC channels [13,14]. "
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    ABSTRACT: As the molecular composition of calcium-release activated calcium (CRAC) channels has been unknown for two decades, elucidation of selective inhibitors has been considerably hampered. By the identification of the two key components of CRAC channels, STIM1 and Orai1 have emerged as promising targets for CRAC blockers. The aim of this study was to thoroughly characterize the effects of two selective CRAC channel blockers on currents derived from STIM1/Orai heterologoulsy expressed in HEK293 cells. The novel compounds GSK-7975A and GSK-5503A were tested for effects on STIM1 mediated Orai1 or Orai3 currents by whole-cell patch-clamp recordings and for the effects on STIM1 oligomerisation or STIM1/Orai coupling by FRET microscopy. To investigate their site of action, inhibitory effects of these molecules were explored using Orai pore mutants. The GSK blockers inhibited Orai1 and Orai3 currents with an IC50 of approximately 4 μM and exhibited a substantially slower rate of onset than the typical pore blocker La3+, together with almost no current recovery upon wash-out over 4 min. For the less Ca2+-selective Orai1 E106D pore mutant, ICRAC inhibition was significantly reduced. FRET experiments indicated that neither STIM1–STIM1 oligomerization nor STIM1–Orai1 coupling was affected by these compounds. These CRAC channel blockers are acting downstream of STIM1 oligomerization and STIM1/Orai1 interaction, potentially via an allosteric effect on the selectivity filter of Orai. The elucidation of these CRAC current blockers represents a significant step toward the identification of CRAC channel-selective drug compounds.
    Cell calcium 12/2012; 53(2). DOI:10.1016/j.ceca.2012.11.005 · 3.51 Impact Factor
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    ABSTRACT: Background: Ca(2+) release-activated Ca(2+) (CRAC) channels, a subfamily of store-operated channels, play an essential role in various diseases such as immune disorders and allergic responses. Objective: The successful treatment of these diseases requires the identification of specific inhibitors. So far, a variety of chemical compounds blocking CRAC have been identified; however, they have all turned out to be less specific. Recently two proteins, STIM1 and ORAI1, have been identified as the essential components that fully reconstitute CRAC currents with a similar biophysical fingerprint. Method: These two proteins and their activation process represent direct targets for the application of specific CRAC inhibitors. Results/conclusion: For drug development, fluorescence microscopy adaptable for high-throughput screening will provide a powerful assay to mechanistically identify potential CRAC inhibitors that act on various stages within the STIM1/ORAI1 activation pathway visualized by fluorescent-tagged proteins.
    Expert Opinion on Drug Discovery 07/2008; 3(7):787-800. DOI:10.1517/17460441.3.7.787 · 3.54 Impact Factor
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