Page 289 - Color_Atlas_of_Physiology_5th_Ed._-_A._Despopoulos_2003

!
kinase cascades that additionally amplify the tions that are exerted either independently or
original signal while receiving further regula- jointly (! B1).
tory signals. IP 3 is a hydrophilic molecule carried via the
2+
Deactivation of the signaling cascade (! A, cytosol to Ca stores within the cell (mainly in
right panel) is induced by the α-subunit in that the endoplasmic reticulum; ! p. 36). IP 3 binds
its GTP molecule splits off GDP and P i after re- there to Ca 2+ channels to open them (! B2),
2+
acting with its GTPase (! A5), and the subunit leading to an efflux of Ca from the intracellu-
subsequently binds to a "γ subunit to again lar stores into the cytosol. In the cytosol, Ca 2+
form the trimeric G protein. Phosphodiesterase acts as a third messenger that regulates various
also converts cAMP into inactive 5!-AMP cell functions, e.g., by interacting with the
Hormones and Reproduction a receptor in the presence of high messenger the cell membrane and has two main func-
(! A4, A6), and phosphatases dephosphorylate
2+
cAMP signaling chain. Many Ca -related ac-
the protein previously phosphorylated by pro-
tivities are mediated by calmodulin, a calcium-
tein kinase A (! A4). Another way to inactivate
binding protein (! pp. 36 and 70).
DAG is a lipophilic molecule that remains in
concentrations is to make the receptor insensi-
tions:
tive by phosphorylating it (desensitization).
! DAG is broken down by phospholipase A2
Cholera toxin inhibits the GTPase, thereby blocking
(PLA-2) to yield arachidonic acid, a precursor of
its deactivating effect on adenylate cyclase (! A5).
eicosanoids (! B3 and p. 269).
This results in extremely high levels of intracellular
2+
Ca -dependent (hence the “C”) because the
to severe diarrhea (! p. 262). Pertussis (whooping
2+
released by IP 3 (see above) is needed to
cough) toxin and forskolin also lead to an increase in
Ca
11 cAMP. When occurring in intestinal cells, this can lead ! DAG activates protein kinase C (PKC). PKC is
the cytosolic cAMP concentration. Pertussis toxin
transfer PKC from the cytosol to the intracellu-
does this by inhibiting G i protein and thereby block- lar side of the cell membrane (! B4). Thus acti-
ing its inhibitory effect on adenylate cyclase, while vated PKC phosphorylates the serine or
forskolin directly activates adenylate cyclase.
Theophylline and caffeine inhibit the conversion of threonine residues of many proteins.
cAMP to 5!-AMP, which extends the life span of cAMP PKC triggers a series of other phosphorylation reac-
and prolongs the effect of the messenger. tions (high signal amplification) that ultimately lead
Certain ion channels are regulated by G s, G i and to the phosphorylation of MAP kinase (mitogen-ac-
other G proteins (G o) with or without the aid of tivated protein kinase). It enters the cell nucleus and
activates Elk-1, a gene-regulating protein. NF-"B,
2+
adenylate cyclase. Some Ca channels are acti- another gene-regulating protein, is also released in
vated by G s proteins and inactivated by G o pro- response to PKC phosphorylation. In addition, PKC
teins, whereas some K channels are activated activates Na /H + antiporters, thereby raising the
+
+
by G o proteins and (the "γ subunits of) G i pro- cellular pH—a stimulus that triggers many other
teins (! p. 83 B). G olf in olfactory receptors, cellular reactions.
transducin in retinal rods (! p. 348ff.), and α- IP 3 and DAG activating messengers include
gustducin in gustatory sensors are also mem- acetylcholine (M 1 and M 3 cholinoceptors), antidi-
uretic hormone = vasopressin (V 1 rec.), epinephrine
bers of the G protein family (! p. 338).
and norepinephrine (α 1 adrenoceptor), bradykinin,
CCK, endothelin, gastrin, glutamate (mGLU 1 and
IP 3 and DAG as Second Messengers mGLU 5 rec.), GRP, histamine (H 1 rec.), leukotrienes,
As in the case of G s proteins, once the first mes- neurotensin, oxytocin and various prostaglandins
senger using this transduction pathway binds (FP, TP, and Ep 1 rec.), serotonin = 5-hydroxytryp-
to its receptor outside the cell, the α q subunit tamine (5-HT 2 rec.), tachykinin, thromboxane A 2.
dissociates from the heterotrimeric G q protein TRH and TSH induce partial activation.
and activates phospholipase C-" (PLC-") on the Deactivation of the signaling cascade can also
inside of the cell membrane (! B1). PLC-" con- be achieved through self-inactivation of the G
verts phosphatidylinositol 4,5-bisphosphate proteins involved (GTP cleavage) and
(PIP 2), to inositol 1,4,5-trisphosphate (IP 3) and phosphatase (see above) as well as by degrada-
diacylglycerol (DAG). IP 3 and DAG function as tion of IP 3.
276 parallel second messengers with different ac-
!
Despopoulos, Color Atlas of Physiology © 2003 Thieme
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