Page 17 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

inositol trisphosphate (IP 3 ),1,3,4,5-inositol tet- Insulin and numerous growth factors acti-
rakisphosphate (IP 4 ), and diacylglycerol (DAG). vate tyrosine kinases (→ A10), which transmit
A membrane-bound phospholipase C (PLC) cellular effects via other kinases, enzymes, and
splits phosphatidylinositol diphosphate (PIP 2 ) transport proteins. The tyrosine kinases can
into IP 3 and DAG after being activated by a so- themselves be part of the receptor, or can at-
called G 0 protein. This reaction is triggered by, tach themselves to the receptor on activation.
among others, epinephrine (α 1 ), acetylcholine Kinases frequently act by phosphorylating
(M 1 receptor), histamine (H 1 receptor), ADH other kinases and thereby trigger a kinase cas-
(V 1 receptor), pancreozymin (CCK), angioten- cade. Thus, the mitogen-activated protein
sin II, thyrotropin-releasing hormone (TRH), kinase (MAP kinase) is activated by another
substance P, and serotonin (S 1 receptor). IP 3 re- kinase (MAP kinase kinase). This “snowball
leases Ca 2+ from intracellular stores. Emptying effect” results in an avalanche-like increase of
of the stores opens Ca 2+ channels of the cell the cellular signal. The p-38 kinase and the Jun
membrane (→ A6). Ca 2+ can also enter the cell kinase that regulate gene expression via tran-
2+
through ligand-gated Ca 2+ channels. Ca , in scription factors are also activated via such
part bound to calmodulin and through subse- cascades. Signal Transmission
quent activation of a calmodulin-dependent Other signaling molecules, such as the small
kinase (CaM kinase), influences numerous cel- G proteins (p 21 Ras) or transcription factors (e.g.,
lular functions, such as epithelial transport, re- c-Jun, c-Fos, c-Myc, NF κ B, AP-1), are important
lease of hormones, and cell proliferation. DAG for signal transduction of growth factors
stimulates protein kinase C (PKC), which is (→ p.14) and in apoptosis (→ p.12).
2+
also activated by Ca . PKC in turn regulates Mutations of the (proto-onco)genes of re-
other kinases, transcription factors (see below) ceptors for growth factors, of tyrosine kinases,
and the cytoskeleton. PKC also activates the of Ras, Jun, or Myc to oncogenes can promote
+
+
Na /H exchanger leading to cytosolic alkali- autonomous cell proliferation, i.e., the devel-
zation and an increase in cell volume. Numer- opment of tumor cells (→ p.14).
ous cell functions are influenced in this way, Some mediators (e.g., the tumor necrosis
+
among them metabolism, K channel activ- factor [TNF] and CD95 [Fas/Apo1] ligand) acti-
ities, and cell division. vate acid sphingomyelinase, which forms cer-
The formation of inositol from inositol amide from sphingomyelin (→ A11). Ceramide
monophosphate is inhibited by the antide- triggers a series of cellular effects, such as acti-
pressant lithium (Li) (→ A7). PKC is activated vation of small G proteins (e.g., Ras), of kinases,
by phorbol esters (→ A8). phosphatases, and caspases, i.e. proteases
Arachidonic acid, a polyunsaturated fatty which cleave proteins at cystein-aspartate
acid, can be split from membrane lipids, in- sites. The effects of ceramide are especially im-
cluding DAG, by phospholipase A (→ A9). Ara- portant in signal transduction of apoptotic cell
chidonic acid itself has some cellular effects death (→ p.12).
(e.g., on ion channels), but through the action Steroid hormones (e.g., aldosterone) do not
of cyclo-oxygenase can also be converted to usually act via receptors on the cell membrane,
prostaglandins and thromboxan, which exert but rather pass easily through the cell mem-
their effect partly by activating adenylyl cy- brane due to their solubility in lipids, and
clase and guanylyl cyclase. Arachidonic acid then bind to intracellular (cytosolic or nuclear)
can also be converted to leukotrienes by lipoxy- receptor proteins (→ A12). The hormone–re-
genase. Prostaglandins and leukotrienes are ceptor complex attaches itself to the DNA of
especially important during inflammation the cell nucleus and in this way regulates pro-
(→ p. 48ff.) and not only serve as intracellular tein synthesis.
messengers, but also as extracellular media-
tors (→ p. 296). Lipoxygenase inhibitors and
cyclo-oxygenase inhibitors, frequently used
therapeutically (e.g., as inhibitors of inflam-
mation and platelet aggregation), inhibit the 7
formation of leukotrienes and prostaglandins.
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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