DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1284
Calcitonin/katacalcin/CGRPgene
5’
E1
E2 E3 E4 E5 E6
3’
mRNA
5’ E1 E2 E3 E4 3’ 5’ E1 E2 E3 E5 E6 3’
Calcitonin/katacalcin
CGRP
SECTION V
Protein
NH 2 82aa CT KC COOH NH 2 82aa CGRP 5aa COOH
Figure 44–6. Alternative splicing of calcitonin/calcitonin gene–related peptide (CGRP).
HORMONES AND HORMONE ANTAGONISTS
32 residues are invariant, including the disulfide bridge and a carboxyl-terminal
proline amide; both structural features are essential
for biological activity. The residues in the middle portion of the molecule
(positions 10–27) are more variable and apparently influence
potency and/or duration of action. Calcitonins derived from salmon
and eel differ from the human hormone by 13 and 16 amino acid
residues, respectively, and are more potent than mammalian calcitonin.
Salmon calcitonin is used therapeutically in part because it is
cleared more slowly from the circulation.
Regulation of Secretion. The biosynthesis and secretion of calcitonin
are regulated by the plasma Ca 2+ concentration. Calcitonin secretion
increases when plasma Ca 2+ is high and decreases when plasma Ca 2+
is low. Multiple forms of calcitonin are found in plasma, including
high-molecular-weight aggregates or cross-linked products. Assays
for the intact monomeric peptide are now available. The circulating
concentrations of calcitonin are low, normally <15 and 10 pg/mL for
males and females, respectively. The circulating t 1/2
of calcitonin is
~10 minutes. Abnormally elevated levels of calcitonin are characteristic
of thyroid C-cell hyperplasia and medullary thyroid carcinoma.
Calcitonin secretion is stimulated by a number of agents,
including catecholamines, glucagon, gastrin, and cholecystokinin,
but there is little evidence for a physiological role for secretion in
response to these stimuli.
Mechanism of Action. Calcitonin actions are mediated by the calcitonin
receptor (CTR), which is a member of the PTH/secretin subfamily of
GPCRs (Lin et al., 1991). Six human CTR subtypes occur through
alternative splicing of coding and noncoding exons (Purdue et al.,
2002). These isoforms exhibit distinct ligand-binding specificity
and/or signal-transduction pathways and are distributed in a tissuespecific
pattern. Of the more abundant isoforms, hCTRI1 - , which lacks
a 16-amino acid insert in the first intracellular loop, preferentially couples
with the G s
–adenylyl cyclase pathway (Gorn et al., 1995). The
hCTRI1 + isoform, which includes this casette, does not couple with
PLC (Naro et al., 1998) and therefore does not activate PKC or trigger
an increase in Ca 2+ . Calcitonin receptors can dimerize with
RAMPs (receptor-activity modifying proteins) to create receptors with
high affinity for amylin (Hay et al., 2005) (Chapter 43).
The hypocalcemic and hypophosphatemic effects of calcitonin
are caused predominantly by direct inhibition of osteoclastic
bone resorption. Although calcitonin inhibits the effects of PTH on
osteolysis, it inhibits neither PTH activation of bone cell adenylyl
cyclase nor PTH-induced uptake of Ca 2+ into bone. Calcitonin interacts
directly with receptors on osteoclasts to produce a rapid and
profound decrease in ruffled border surface area, thereby diminishing
resorptive activity.
Depressed bone resorption reduces urinary excretion of Ca 2+ ,
Mg 2+ , and hydroxyproline. Plasma phosphate concentrations are
lowered owing also to increased urinary phosphate excretion. Direct
renal effects of calcitonin vary with species. Acute administration of
pharmacological doses of calcitonin increases urinary calcium excretion,
whereas calcitonin inhibits renal calcium excretion at physiological
concentrations. In humans, calcitonin increases fractional
urinary calcium excretion in a dose-dependent manner in subjects
given a modest calcium load (Carney, 1997).
Figure 44–7. Comparison of calcitonins from several species. Calcitonin is a 32-amino-acid polypeptide with a disulfide bond between
residues 1 and 7 and a proline-amide at the C-terminus. The figure highlights the differences in amino acid sequence between human
calcitonin and calcitonins of other species; lack of an entry indicates identity with human calcitonin. Salmon calcitonin is ~20 times
more potent in humans than is human calcitonin.