Hello, I'm Bob Nissenson from
the University of California and
the Veterans Affairs Medical Centre
in San Francisco.
This lecture will focus on two fascinating
proteins, parathyroid hormone and
parathyroid hormone related protein,
the genes in coding these two molecules
are presumed to be derived from
a common ancestral gene, but
the functions of the proteins have
diverged markedly over evolutionary time.
Much of the research in my laboratory over
the years has been devoted to gaining
a better understanding
of the physiology and
mechanism of action of these molecules.
PTHrP share a number of common features.
They are both secreted polypeptides and
they share a limited degree of amino acid
homology in their N-terminal domain.
They have a sufficient degree of
conformational homology to allow
them to bind to and activate
a common G-protein-coupled receptor,
the PTH1 receptor.
PTH and PTHrP produce similar
defects in calcium homeostasis,
including high blood calcium or
hypercalcemia when overproduced
in pathological states in vivo.
However, there are major
differences between PTH and PTHrP,
they differ with respect to
their physiological roles,
sites of expression,
mode of action and secretory control.
The major physiological role of
PTH in terrestrial vertebrates is
to maintain adequate
levels of plasma calcium
in the face of a calcium poor
PTHrP has a large number of functions,
including the regulation of cartilage
maturation during endochondral
bone formation, the promotion of
the proper morphogenesis of a number of
tissues during development and
the relaxation of smooth muscles.
PTH is normally produced only
by the parathyroid glands.
PTHrP production is widespread and
is adjacent to sites where it acts.
PTH functions as a systemic
endocrine hormone, by contrast,
PTHrP acts locally in a paracrine fashion.
The major factor controlling
the secretion of PTH is
the concentration of
calcium in the circulation.
PTHrP production is regulated
by specific local cues.
The full length secreted form of
PTH consists of 84 amino acids.