Inositol 1,4,5-trisphosphate (InsP3) ligation of its receptor (InsP3R) results in release of stored intracellular calcium. This store-depletion couples to subsequent calcium influx via the store-operated calcium current ICRAC. Calcium, derived from both intracellular store release and influx via ICRAC, regulates a remarkably diverse range of cellular processes including growth, differentiation, death, and the acute effector responses of immune system cells to antigen. InsP3 levels are tightly controlled, and calcium release and influx responses can be dissociated by their differential sensitivity to cytosolic InsP3 levels. Modulation of either of these calcium signals for therapeutic purposes may be achieved via manipulation of the threshold for their generation. Here we propose to investigate the mechanisms that set the response threshold for InsP3- driven calcium release and influx. We hypothesize that both intrinsic properties of the InsP3R, and the environment provided by enzymes that metabolize InsP3, may be critical determinants of the specific activity of a given concentration of InsP3. Moreover, we will investigate the contribution of these factors to the generation of specific calcium-store sub-compartments with different response thresholds, such as the calcium store that couples to ICRAC activation (the 'CRAC store'). This compartment is notable for its low sensitivity (i.e., high threshold) to InsP3.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050200-02
Application #
6868963
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Mallia, Conrad M
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost
Name
Queen's Medical Center
Department
Type
DUNS #
054787481
City
Honolulu
State
HI
Country
United States
Zip Code
96813
Beck, Andreas; Fleig, Andrea; Penner, Reinhold et al. (2014) Regulation of endogenous and heterologous Ca²? release-activated Ca²? currents by pH. Cell Calcium 56:235-43
Thiel, Markus; Lis, Annette; Penner, Reinhold (2013) STIM2 drives Ca2+ oscillations through store-operated Ca2+ entry caused by mild store depletion. J Physiol 591:1433-45
Lis, Annette; Zierler, Susanna; Peinelt, Christine et al. (2010) A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J Gen Physiol 136:673-86
Peinelt, Christine; Beck, Andreas; Monteilh-Zoller, Mahealani K et al. (2009) IP(3) receptor subtype-dependent activation of store-operated calcium entry through I(CRAC). Cell Calcium 45:326-30
Peinelt, Christine; Lis, Annette; Beck, Andreas et al. (2008) 2-Aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels. J Physiol 586:3061-73
Parvez, Suhel; Beck, Andreas; Peinelt, Christine et al. (2008) STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB J 22:752-61
Lis, Annette; Peinelt, Christine; Beck, Andreas et al. (2007) CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol 17:794-800
Cheng, Henrique; Beck, Andreas; Launay, Pierre et al. (2007) TRPM4 controls insulin secretion in pancreatic beta-cells. Cell Calcium 41:51-61
Vig, Monika; Beck, Andreas; Billingsley, James M et al. (2006) CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16:2073-9
Peinelt, Christine; Vig, Monika; Koomoa, Dana L et al. (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771-3

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