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

1278 removed by extrarenal mechanisms. Rather than competing with
PTH(1–84) binding at the receptor, PTH(7–84) may cause the PTH
receptor to internalize from the plasma membrane in a cell-specific
manner (Sneddon et al., 2003).
During periods of hypocalcemia, more PTH is secreted and
less is hydrolyzed. In this setting, PTH(7–84) release is augmented.
In prolonged hypocalcemia, PTH synthesis also increases, and the
gland hypertrophies.
PTH(1–84) has a t 1/2
in plasma of ~4 minutes; removal by the
liver and kidney accounts for ~90% of its clearance. Proteolysis of
PTH (in the storage granule and in plasma) generates smaller fragments
(e.g., a 33–36 amino acid N-terminal fragment that is fully
active, a larger C-terminal peptide, and PTH[7–84]). Much of what
circulates in the blood and is measured by older RIAs is the inactive
C-terminal fragment that has a longer t 1/2
than the active N-terminal
fragment or the intact PTH(1–84). Second-generation enzyme-linked
immunosorbent assays for PTH, by contrast, can distinguish among
these forms, but the clinical value of such information and whether
it should affect therapeutic intervention remains controversial
(D’Amour, 2008; Herberth et al., 2009).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Parathyroid Hormone
Parathyroid hormone (PTH) is a polypeptide hormone
that helps to regulate plasma Ca 2+ by affecting bone
resorption/formation, renal Ca 2+ excretion/reabsorption,
and calcitriol synthesis (thus GI Ca 2+ absorption).
History. Sir Richard Owen, the curator of the British Museum of
Natural History, discovered the parathyroid glands in 1852 while
dissecting a rhinoceros that had died in the London Zoo. Credit for
discovery of the human parathyroid glands usually is given to
Sandstrom, a Swedish medical student who published an anatomical
report in 1890. In 1891, von Recklinghausen reported a new bone
disease, which he termed “osteitis fibrosa cystica,” which Askanazy
subsequently described in a patient with a parathyroid tumor in 1904.
The glands were rediscovered a decade later by Gley, who determined
the effects of their extirpation with the thyroid. Vassale and
Generali then successfully removed only the parathyroids and noted
that tetany, convulsions, and death quickly followed unless calcium
was given postoperatively.
MacCallum and Voegtlin first noted the effect of parathyroidectomy
on plasma Ca 2+ . The relation of low plasma Ca 2+ concentration
to symptoms was quickly appreciated, and a comprehensive
picture of parathyroid function began to form. Active glandular
extracts alleviated hypocalcemic tetany in parathyroidectomized animals
and raised the level of plasma Ca 2+ in normal animals. For the
first time, the relation of clinical abnormalities to parathyroid hyperfunction
was appreciated.
Whereas American and British investigators used physiological
approaches to explore the function of the parathyroid glands,
German and Austrian pathologists related the skeletal changes of
osteitis fibrosa cystica to the presence of parathyroid tumors; these
two investigational approaches arrived at the same conclusions, as
has been recounted by Carney (1997).
Chemistry. PTH molecules of all species are all single polypeptide
chains of 84 amino acids with molecular masses of ~9500 Da.
Biological activity is associated with the N-terminal portion of the
peptide; residues 1–27 are required for optimal binding to the PTH
receptor and hormone activity. Derivatives lacking the first and second
residue bind to PTH receptors but do not activate the cyclic AMP
or IP 3
–Ca 2+ signaling pathways. The PTH fragment lacking the first
six amino acids inhibits PTH action.
Synthesis, Secretion, and Immunoassay. PTH is synthesized as a
115-amino-acid translation product called preproparathyroid hormone.
This single-chain peptide is converted to proparathyroid hormone
by cleavage of 25 amino-terminal residues as the peptide is
transferred to the intracisternal space of the endoplasmic reticulum.
Proparathyroid hormone then moves to the Golgi complex, where it
is converted to PTH by cleavage of six amino acids. PTH(1-84)
resides within secretory granules until it is discharged into the circulation.
Neither preproparathyroid hormone nor proparathyroid hormone
appears in plasma. The synthesis and processing of PTH have
been reviewed (Jüppner et al., 2001).
A major proteolytic product of PTH is PTH(7–84). PTH(7–84)
and other amino-truncated PTH fragments accumulate significantly
during renal failure in part because they are normally cleared from the circulation
predominantly by the kidneys, whereas intact PTH is also
Physiological Functions. The primary function of PTH is to maintain
a constant concentration of Ca 2+ and P i
in the extracellular fluid. The
principal processes regulated are renal Ca 2+ and P i
absorption, and
mobilization of bone Ca 2+ (Figure 44–3). PTH also affects a variety
of tissues not involved in mineral ion homeostasis that include cartilage,
vascular smooth muscle, placenta, liver, pancreatic islets,
brain, dermal fibroblasts, and lymphocytes. The actions of PTH on
its target tissues are mediated by at least two receptors. The PTH 1
receptor (PTH1R or PTH/PTHrP receptor) also binds PTH-related
protein (PTHrP); the PTH 2
receptor, found in vascular tissues, brain,
pancreas, and placenta, binds only PTH. Both of these are GPCRs
that can couple with G s
and G q
in cell-type specific manners; thus
cells may show one, the other, or both types of responses. There is
also evidence that PTH can activate phospholipase D through a
G 12/13
–RhoA pathway (Singh et al., 2005). A third receptor, designated
the CPTH receptor, interacts with forms of PTH that are truncated
in the amino-terminal region, contain most of the carboxy
terminus, and are inactive at the PTH 1
receptor; these CPTH receptors
reportedly are expressed on osteocytes (Selim et al., 2006).
Regulation of Secretion. Plasma Ca 2+ is the major factor regulating
PTH secretion. As the concentration of Ca 2+ diminishes, PTH secretion
increases. Sustained hypocalcemia induces parathyroid hypertrophy
and hyperplasia. Conversely, if the concentration of Ca 2+ is
high, PTH secretion decreases. Studies of parathyroid cells in culture
show that amino acid transport, nucleic acid and protein synthesis,
cytoplasmic growth, and PTH secretion are all stimulated by low
concentrations of Ca 2+ and suppressed by high concentrations. Thus,
Ca 2+ itself appears to regulate parathyroid gland growth as well as
hormone synthesis and secretion.
Changes in plasma Ca 2+ regulate PTH secretion by the
plasma membrane–associated calcium-sensing receptor (CaSR) on
parathyroid cells. The CaSR is a GPCR that couples with G q
and G i
.
Occupancy of the CaSR by Ca 2+ thus stimulates the G q
-PLC-IP 3
-
Ca 2+ pathway leading to activation of PKC; this results in inhibition
of PTH secretion, an unusual case in which elevation of cellular Ca 2+
inhibits secretion (another being the granular cells in the juxtaglomerular
complex of the kidney, where elevation of cellular Ca 2+