The Cell - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 22

(C)

Inositol phospholipid

Signal

Activated α
subunit

G protein - linked
receptor

Diacyl
glycerol

GTP

Activated PKC

Activated
phospholipase C

Inositol triphosphate

Ca 2+

Open
Ca 2+ channel

Endoplasmic recticulum

Figure 1.9 ( Continued ).

cyclic AMP tremendously by synthesis from ATP. Cyclic AMP in turn produces
its effects by activation of a protein called protein kinase A. The protein kinase is
activated by binding with cyclic AMP, and the activated kinase then phosphorylates
specific proteins at the serine or threonine residues. This alters their activity and in
different cells a wide variety of responses can be seen ( Fig. 1. B) [6-66] .
Other G protein-coupled receptors mediate their effects via phospholipase C
present in the membrane. The activated phospholipase C produces two messengers,
inositol 1,,5 trisphosphate and diacylglycerol, by hydrolysis of membrane inosi-
tol phospholipid. The trisphosphate moiety is hydrophilic and diffuse through the
cytosol, to release calcium ions from ER, whereas the diacylglycerol remains in the
plasma membrane only. The increased cytosolic calcium level, along with diacylg-
lycerol, activates protein kinase C, which subsequently phosphorylates and activates
several other intracellular proteins ( Fig. 1. C).
The several signal-transducing mechanisms involve calcium at one stage or
another. Calcium is a very important second messenger, and its levels are grossly
different across the membranes. These gradients are maintained by active membrane
pumps. The effects of calcium are mediated through calcium-binding proteins; a fre-
quently involved example is calmodulin. The calcium binds with calmodulin, and in
turn this activated complex activates calcium/calmodulin-dependent protein kinase,
which subsequently phosphorylates other proteins [6-1] .

1.6.3 Enzyme-Linked Receptors
Enzyme-linked receptors are also transmembrane proteins, and the extracellular
ligands bind to them on the extracellular side. They comprise a very large family, and
a major subclass includes receptor tyrosine kinases that phosphorylate the tyrosine