Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 222

high calcium concentrations have inhibitory effects on the channel ( Taylor
and Tovey, 2010 ). Furthermore, the IP3R is modulated by covalent modifi-
cations, such as phosphorylation of key residues by PKA, ERK and/or PKC
( Patterson et al., 2004 ). Nucleotides, such as ATP and NADH, also play an
important role in channel modulation, linking the energetic needs of the
cell to IP3R activity ( Patterson et al., 2004 ; Taylor and Tovey, 2010 ).
Finally, apoptotic proteins like caspase-3, calpains, and cytochrome c
interact with and regulate IP3Rs, thereby contributing to life or death deci-
sions of the cell ( Patterson et al., 2004 ; Taylor et al., 2004 ).
2.2.2.4. Calcium Buffering
Calcium-binding chaperones, such as calreticulin and calnexin, also play
an important role in ER luminal calcium regulation. By sequestering free
calcium, chaperones work as ion buffers. Owing to the efficient actions
of these proteins, the free calcium concentration in the ER is only 50-
500 µM, whereas the actual luminal calcium concentration ranges around
2 mM ( Coe and Michalak, 2009 ).
Calreticulin, the glucose-regulated protein 94 (GRP94) and BiP/
GRP78 are the most abundant calcium-binding chaperones in the ER.
These proteins bind calcium with high affinity in their C-terminal domain
where they possess several calcium-binding sites ( Michalak et al., 2009 ).
In the SR, the main chaperone responsible for calcium regulation is the
calreticulin homolog, calsequestrin, which is of great importance in muscle
contraction, not only because of its buffering capacity but also its ability to
modulate RyR function ( Michalak et al., 2009 ).
2.2.3. Lipid Synthesis at Endoplasmic Reticulum
Lipids fulfill several functions essential for cellular homeostasis. They are
employed as a backup energy source, signaling molecules, and as membrane
components, among other functions. Cellular lipids are quite heterogeneous,
existing in the form of fatty acids, phospholipids, cholesterol, and sphingolipids
( Laplante and Sabatini, 2009 ).The ER plays an essential role in lipid biogenesis,
mainly in the synthesis of glycerophospholipids and sphingolipids, the major
components of biological membranes. ER enzymes such as glycerol-3-phos-
phate acyltransferase-like and 1-acylglycerol-3-phosphate- O -acyltransferase
transform glycerol and fatty acids into phospholipid precursors, such as triglyc-
erides and diacylglycerol phosphate (DGP). In the ER lumen, DGP is dephos-
phorylated by phosphatidic acid phosphatases to form diacylglycerol (DG),
which is converted to phosphatidylcholine and phosphatidylethanolamine.