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Selected Publication:
Shrestha,N.
Characterization of the molecular role of TRICA in oscillatory Ca2+ signaling
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 80
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- Authors Med Uni Graz:
- Shrestha Niroj
- Advisor:
- Groschner Klaus
- Malli Roland
- Sedej Simon
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- Abstract:
- Trimeric intracellular cation (TRIC) channels reside in the sarco/endoplasmic reticulum (SR/ER) and have been proposed to sense luminal Ca2+ and modulate ER Ca2+ release by providing counterion flux. The TRICA isoform is expressed predominantly in the excitable tissues and appears to modulate the oscillatory Ca2+ signaling. This thesis is aimed at elucidating the molecular functions of TRICA and provides evidence for a novel concept of frequency modulation in oscillatory Ca2+ signaling, based on dynamic targeting of TRICA into STIM1/Orai1 complexes. Using a HEK293 reconstitution approach, we identified TRICA modulates the amplitude and frequency of RyR2-mediated Ca2+ oscillations and IP3R-induced cytosolic signals by attenuating store-operated Ca2+ entry (SOCE). Further, TRICA-dependent delay in ER Ca2+ refilling contributes to shaping the pattern of Ca2+ oscillations. Upon ER Ca2+ depletion, TRICA co-migrates with STIM1, clusters with STIM1 and Orai1 within ER-plasma-membrane (PM) junctions, and impairs assembly of STIM1/Orai1 complex, causing a decrease in Orai1-mediated Ca2+ current and SOCE. Together, our findings demonstrate that TRIC-A is a negative regulator of STIM1/Orai1 function. Thus, upregulation of SOCE could contribute to muscle disorders associated with loss of TRICA.