Biomedical Engineering Reference
In-Depth Information
2.2.4.2 PTH Receptor Signal Transduction
and Nuclear Effects
form of the peptide is
amino acids in length.
PTHrP, on the other hand, is an autocrine/
paracrine factor that was fi rst discovered as the
primary cause of malignant hypocalcemia in
many cancers [
84
Receptor activities are modulated through
interaction with heterodimeric (
]. It is normally expressed
during development and in many postnatal
tissues, including cardiac, vascular, mammary,
cartilage, and renal tissues, as well as a number
of other epithelial surfaces. The mature form of
PTHrP is
28
) G pro-
teins that activate or inhibit cyclase production
of cAMP. The levels of cAMP then control the
activity of protein kinase A (PKA), which serves
as the cAMP intracellular second signal trans-
ducer [
α
,
β
,
γ
amino acids in length. Even
though PTH and PTHrP bind to the same
receptor, the two molecules share only a limited
sequence homology along the fi rst
141
]. The activation of the receptor by
ligand binding also activates phospholipases
C
77
. Activated phospholipase
generates diacylglycerol and
β
through G
α
q
11
amino
acids of their amino terminal sequences
and diverge considerably in their carboxyl
domains.
The effects of the major calcitropic hormone
PTH on skeletal cells are very important clini-
cally, owing to the role played by the skeleton
in mineral homeostasis. Both molecules have
similar systemic effects on mineral metabo-
lism, yet they differ in amino acid composition
and physiological function. PTH and PTHrP
share a common receptor (PTHR
34
1
,
4
,
5
-inositol tri-
phosphate (IP
). These two molecules activate
both protein kinase C (PKC) and Ca
2
+
release.
Study of the “cross-talk” between the PKA-
arm, PKC kinases [
3
], and Ca
2
+
will likely sort
out the many parallel and sometimes antago-
nistic functions of the PTH and PTHrP ligands
in different target-cell populations [
125
].
At the nuclear level, both the PKA and the
PKC families of kinases mediate their actions
through the phosphorylation of members of
the leucine zipper family of transcription
factors [
76
) and, when
in the circulation, are primarily targeted to the
kidney and skeleton [
1
]. These transcription factors, when
phosphorylated, may activate or inhibit the
transcription of specifi c genes [
125
]. In the kidney, PTH
and PTHrP bring about their calcitropic effects
by stimulating calcium reabsorption and phos-
phate excretion in the distal end of the collect-
ing tubules. They also regulate formation of
the active vitamin D
3
metabolite,
62
] and
may be classifi ed into two broad groups: the
cAMP response element-binding protein family
(CREBs) and members of the AP-
113
,
132
family. The
CREBs include the CREB, CREM, and ATF
classes of factors; the primary members of the
AP-
1
-
dihydroxyvitamin D
3
by activating the enzyme
that carries out the
1
,
25
-
hydroxyvitamin D
3
in the proximal tubules.
This leads to a rise in serum calcium and a
lowering of phosphate level. The effects on the
skeletal system are less well understood. PTH
binds to the receptors of osteoblasts [
1
α
-hydroxylation of
25
1
family include fos, jun, and fra [
8
,
77
,
125
,
131
]. In general, the actions of PKA are
mediated through the phosphorylation of
members of the CREB family, while PKC
appears to act on members of the AP-
,
173
,
205
family.
However, phosphorylation may not be restricted
to one type of kinase or individual factors. The
factors are active when dimeric. Members of
both families can undergo specifi c heterodi-
merization with one another [
1
],
which produce paracrine factors that induce
increased activation and recruitment of
osteoclasts.
PTH and PTHrP, like other peptide hor-
mones, mediate their effects through interac-
tion with a receptor. Two forms of this receptor
are known, but the two peptides interact pri-
marily with PTH
177
]. Heterodi-
merization gives rise to a diversity of specifi c
transcription factors. As a result, genes may
be expressed or silenced in a tissue-specifi c
fashion in response to common second signals
[
125
R. This receptor has seven
transmembrane domains and is closely related
to a subset of similar receptors that include the
calcitonin and secretin receptors [
1
]. Similarly targeted changes or ablation of
these transcriptional regulators give rise to
specifi c skeletal tissue phenotypes.
Extensive data have been accumulated to
suggest that the leucine zipper family of tran-
scription factors plays a major role in the regu-
lation of gene expression and development in
77
]. PTH and
PTHrP bind almost identically to the receptor,
which has both endocrine and autocrine/para-
crine functions in the tissues in which it is
expressed [
65
2
].
