720
chapter 30
Endocrine Metabolism I: Introduction
PMG
F IG U R E 3 0 -1 0
Inositol metabolism. An inositol phosphate cycle converts inositol
1,4,5-trisphosphate (IPj) to free inositol, which can then combine with
CDP-diacylglycerol (CDP-DAG) to re-form phosphatidylinositol (PI).
Inositol 1,4-bisphosphate (IP
2
) and inositol 1-phosphate (IP) are
intermediates in this cycle. The CDP-DAG produced in the lipid cycle returns
diacylglycérol for resynthesis of PI. It is uncertain whether arachidonic acid
is released by hydrolysis of diacylglycérol, with release of a monoglyceride
(MG), or of phosphatidic acid (PA), with release of a phosphomonoglyceride
(PMG). The futile cycling of PI, phosphatidylinositol 4-phosphate (PIP),
and phosphatidylinositol 4,5-bisphosphate (PIP
2
) maintains a supply of
PIP
2
to generate diacylglycérol and IPs in response to agonist binding.
The enzymes involved are 1, phosphatidylinositol kinase; 2, PIP kinase; 3,
PIP
2
phosphomonoesterase; 4, PIP phosphomonoesterase; 5, PIPs
phosphodiesterase (phospholipase C);
6
, IP
3
phosphatase; 7, IP
2
phosphatase;
8
, IP phosphatase; 9, CDP-diacylglycerol inositol
phosphatidate transferase (phosphatidylinositol synthase);
1 0
, diacylglycérol
kinase; 11, CTP-phosphatidate cytidyl transferase; 12, diacylglycérol lipase;
and 13, phospholipase A
2
. [Modified and redrawn with permission from
M. J. Berridge and R. F. Irvine,
I n o s i t o l t r i p h o s p h a t e , a n o v e l s e c o n d
m e s s e n g e r i n c e l l u l a r s i g n a i t r a n s d u c t i o n . N a t u r e
312,
315 (1984). © 1984
by Macmillan Magazines Ltd.]
of IP
3
, making IP
3
the second messenger and calcium the
third messenger. In the endoplasmic reticulum, IP
3
seems
to increase efflux of Ca2+. Amplification occurs since an
estimated
1 0 - 2 0
calcium ions are released from liver en-
doplasmic reticulum by each IP
3
molecule. IP
3
is rapidly
hydrolyzed to free inositol, which is used for resynthesis
of PI (Chapter 19). Removal of the 1
-phosphate is blocked
by lithium, with accumulation of inositol
1
-phosphate and
depletion of myoinositol pools. The effect is most marked
in the brain, where lithium also inhibits
de novo
synthesis
of myo-inositol and plasma inositol is unable to cross the
blood-brain barrier. Lithium carbonate, used to treat bipo-
lar affective disorders, may have its therapeutic effect by
inhibition of the phosphatidylinositol system.
In several types of cells, stimulation of plasma mem-
brane receptors coupled to phosphoinositide turnover not
only triggers a rapid mobilization of intracellular Ca2+
as discussed above, but also a prolonged mobilization.
The latter is dependent extracellular Ca2+, and another
metabolite of inositol, namely, inositol tetrakisphosphate
(IP
4
),or Ins(l,
3
,
4
,
5
)P
4
, has been implicated in the trans-
port of extracellular Ca2+. The molecular mechanism of
this process is nuclear. IP4, unlike IP
3
, cannot mobilize
Ca2+ from endoplasmic reticulum. IP
4
metabolism con-
sists of its synthesis from IP
3
by a novel, specific ATP-
dependent kinase and its conversion to inactive metabolite
Ins(l,
3
,
4
)P
3
by a phosphatase. The regulation of kinase
and phosphatase activity may be of importance in con-
trolling the intracellular events. Diacylglycérol released
by phospholipase C may increase protein phosphoryla-
tion. Protein kinase C (C-kinase) is a monomeric enzyme
(M.W. 82,000) found free in the cytosol in most tissues
except brain, kidney, and liver, where it is predominantly
membrane-bound. Diacylglycérol increases both the bind-
ing of protein kinase C to the inner surface of the plasma
membrane and the sensitivity of the kinase to activation
by Ca2+ and phosphatidylserine. The effects of DAG re-
lated to protein phosphorylation are thought to be mediated
by this kinase. Tumor-promoting phorbol esters such as
12-O-tetradecanoylphorbol-13-acetate (ingredient in cro-
ton oil that promotes skin tumor production by carcino-
gens) can directly activate protein kinase C, mimicking
DAG and bypassing the receptors. When activated by
phorbol esters, protein kinase C phosphorylâtes cytoso-
lic myosin light-chain kinase (Chapter 21 ) and other pro-
teins, particularly those related to secretion and prolifera-
tion. When activated by DAG, the kinase phosphorylâtes
a number of proteins
in vivo,
but its physiological sub-
strates are unknown. DAG is removed by phosphorylation
to phosphatidic acid or by hydrolysis to monoacylglycerol
and free fatty acid.
In addition to the effects of DAG and phorbol esters on
protein kinase C, some evidence links malignant transfor-
mation by some oncogene products to phosphoinositide
metabolism. Platelet-derived growth factor, the product
of the
sis
oncogene, stimulates inositol lipid metabolism.
Products of the
src
and
ras
oncogenes may be phos-
phoinositide kinases, which increase the concentration of
PIP
3
and provide more substrate for phospholipase C.
The product of the
ras
gene is a GTP-binding protein
(G-protein) involved in receptor activation of PIP
2
hydrol-
ysis. A point mutation activates the
ras
oncogene, and the
resulting oncogene product binds GTP but lacks GTPase
activity. This abnormal protein could activate PIP
2
hydrol-
ysis independently of receptor occupancy.
Following these early events initiated by binding of a
calcium-mediated hormone to its receptor, a transient rise
in cytosolic calcium concentration and a more prolonged
increase in DAG concentration occur. There is also a pro-
longed four- to fivefold increase in Ca2+ flux across the
