|
| Research Summary
|
Calcium is the major signaling molecular in the cell. It controls many cellular functions such as fertilization, cell proliferation and differentiation,
secretion, cellular metabolism, muscle contraction and also apoptosis. Our laboratory is interested in calcium signaling mediated by intracellular calcium
release channel including the inositol trisphosphate receptor (InsP3R), ryanodine receptor (RyR) and the newly discovered two-pore channel
(TPC). Mutation of these channels causes neurological defects (epilepsy), malignant hyperthermia and heart diseases; and in the case
of InsP3R and RyR, alternations of these pathway have been associated with Alzheimer’s disease. We use novel electrophysiological
method to study the gating and regulation of these channels in the native membrane. In combination with the molecular and biochemical
assays, we recently discovered interactions of the InsP3R with presenilins (proteins involved in Alzheimer’s disease) and mutant
presenilin exerts stimulatory effect on InsP3R single channel activity (Fig. 1)
The enhanced single channel activity is thereby increased the cellular calcium responses (Video Clip)and promoted amyloidogenic Aβ42 formations (Fig.2).
We are now focusing on understanding the molecular mechanisms for calcium disruption in Alzheimer’s disease. Similar approach will be employed to study disease pathogenesis associated with RyR and TPC channels. |
Fig.1: Representative InsP3R single channel recording from isolated primary neuron from control C57 or AD mouse (3xTg-AD) harboring presenilin M146L mutation. InsP3R was activated by 10 µM InsP3 in the pipette and holding potential is +40 mV. Arrows indicate zero current level.
Video Clip: Representative spontaneous calcium oscillations imaged from control (CTL) or presenilin M146L mutated cells (M146L). Cells were loaded with 2 µM Fura-2 AM, alternatively excited with 340 and 380 nm wavelength and emitted light was captured at 510 nm. The video is showing the spontaneous calcium oscillations of the cells at the emission channel of 380 nm excitation. |
Fig.2: Hypothetical molecular mechanism of enhanced Aβ production due to Ca2+ disruption in presenilin mutated cell.
In normal cells, Ca2+ signals are tightly regulated in time, space, and amplitude. In AD cells, mutant PS exerts stimulatory effects on InsP3R gating with prolonged channel openings which generates exaggerated Ca2+ signaling by promoting additional release channel recruitment by CICR. Increased cytosolic Ca2+ concentration promotes Aβ production, which, together with mutant PS-enhanced production of amyloidogenic Aβ, results in plaque formation. |
Selected publications
- Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE and Foskett JK (2010) Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 3: ra22
- Cardenas C, Miller RA, Smith I, Bui T, Molgo J, Muller M, Vais H, Cheung KH, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR and Foskett JK (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142: 270-283
- Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM and Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58: 871-883
- Foskett JK, White C, Cheung KH and Mak DO (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87: 593-658
- van Rossum DB, Patterson RL, Cheung KH, Barrow RK, Syrovatkina V, Gessell GS, Burkholder SG, Watkins DN, Foskett JK and Snyder SH (2006) DANGER, a novel regulatory protein of inositol 1,4,5-trisphosphate-receptor activity. J Biol Chem 281: 37111-37116
- Cai C, Lin P, Cheung KH, Li N, Levchook C, Pan Z, Ferrante C, Boulianne GL, Foskett JK, Danielpour D and Ma J (2006) The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem 281: 16649-16655
|
|
