section 30.5
Types of Hormone Receptors
719
Receptor
F IG U R E 3 0 -8
Gq protein-coupled phosphatidylinositol-Ca2+ pathway. The binding of a hormone at a specific receptor site results in
the activation of G-protein which, in turn, activates phospholipase C via GQa.GTP-protein. The action of phospholipase C
on phosphatidylinositol 4,5-bisphosphate (PIP
2
) yields inositol trisphosphate (IP
3
) and diacylglycérol (DAG) which,
along with phosphatidylserine (PS), activates protein kinase C. IP
3
binds to receptors on SER, releasing Ca2+ which, in
turn, activates another set of protein kinases. +, Activation.
of phosphoinositides in the plasma membrane. The
pathway is initiated by the binding of extracellular
messengers to specific receptors located on the plasma
membrane and activating G-proteins (e.g.,
G q ).
The ac-
tivated GQa.GTP-protein, in turn, activates phospholipase
C, which catalyzes hydrolysis of phosphatidylinositide
4,5-bisphosphate,
initiating
the
intracellular
second-
messenger effects (Figure 30-8). The action of phospho-
lipase C results in the formation of two products, inosi-
tol 1,4,5,-trisphosphate (IP
3
) and diacylglycérol (DAG),
which function as intracellular messengers (Figure 30-9).
Most of the DAG released in response to stimulation of
calcium-mobilizing receptors contains arachidonic acid
esterified to C
2
of the glycerol. This arachidonate may
0
»
o
11
CH, - O -C -R ,
R2—C-O -CH
o
II
CH,-Ot p- o - c,
• I
r
' O'
H
H
0
P - 0
1
O'
F IG U R E 3 0 -9
Structure of phosphatidylinositol 4,5-bisphosphate. Hydrolysis at the dotted
line is catalyzed by phospholipase C and releases diacylglycérol and inositol
1,4,5-trisphosphate, which are the intracellular second messengers.
be released from DAG by diacylglycérol lipase or from
phosphatidic acid by phospholipase A
2
, following phos-
phorylation of DAG. It can then serve as a substrate for
the synthesis of eicosanoids (prostaglandins, prostacy-
clins, thromboxanes, and leukotrienes; Chapter 18), which
also modulate a number of physiological functions. These
reactions are part of lipid and phosphoinositide cycles
(Figure 30-10). Many extracellular messengers in a
variety of cells activate this “leak” pathway. They include
acetylcholine (many tissues); epinephrine, angiotensin,
and vasopressin (liver); angiotensin (adrenal cortex); glu-
cose (pancreatic islets); photons (photoreceptor cells); and
several different substances in neutrophils, leukocytes, and
platelets. Many of the membrane receptors linked to phos-
phoinositide metabolism also activate guanylate cyclase,
but the mechanism and function of this activation remain
unknown.
The starting point of these reactions is phosphatidyli-
nositol 4,5-bisphosphate (PIP
2
; Figure 30-10), which is
synthesized from phosphatidylinositol (PI) in two steps
catalyzed by specific kinases. The phosphates are removed
by specific phosphomonoesterases setting up futile cycles.
Stimulation of phospholipase C by binding of an agonist to
its receptor hydrolyzes PIP
2
, releasing IP
3
and DAG (usu-
ally 1
-stcaroyI-2-arachidonyl-.vn-glyccroI). IP
3
stimulates
the release of Ca2+, predominantly from the endoplasmic
reticulum, and may increase plasma membrane permeabil-
ity to Ca2+ in some cells. In most cells studied, the rise in
level of cytosolic Ca2+ is preceded by an increase in that
