The
Section on Hormonal Regulation studies the mechanisms of action of peptide
hormones, in particular, angiotensin II (Ang II) and gonadotropin-releasing
hormone (GnRH). This work involves the analysis of receptor-mediated
processes including G protein-dependent and other intracellular signaling
pathways, and of receptor desensitization, endocytosis, and trafficking.
Ang II is a major regulator of cardiovascular, renal, adrenal, and neuronal
function, and acts through two distinct seven transmembrane receptors
(AT1and AT2). The AT1
receptor is widely expressed and accounts for the known, largely Gq-mediated,
physiological actions of Ang II. In contrast, the AT2
receptor has a more limited distribution, does not internalize, and
does not signal through Gq or Gs-coupled
transduction pathways. Instead, the AT2 receptor
activates tyrosine phosphatases and exerts inhibitory actions on MAP
kinases that counteract the proliferative responses elicited by Ang
II and growth factors. Current research includes structure-function
analyses of the AT1 and AT2
receptors and the mechanisms controlling their phosphorylation and signaling,
and studies on the endocytosis and processing of the AT1
receptor.
The
physical and functional interactions between the AT1 and AT2 receptors,
and those between AT1 and growth factor receptors, are also investigated.
In addition, the pathways by which Ang II and growth factors (EGF and
PDGF) stimulate MAP kinase activity are analyzed in adrenal, hepatic,
and transfected cells expressing native and mutant Ang II receptors.
These studies are aimed at the elucidation not only of the regulation
and properties of the AT1 and AT2 receptors, but also at the understanding
of interactions between the two Ang II receptors and other cell-membrane
receptors, in particular, those for growth factors such EGF and PDGF.
A major component of this research is the exploration of physical as
well as functional interactions of the AT receptors with each other,
as well as with tyrosine kinase receptors expressed at the plasma membrane.
Studies
on the GnRH receptor include the characterization of its structure-function
and signaling properties, and of its role in the pituitary and hypothalamus
in the regulation of gonadotropin secretion. The control of mammalian
reproduction depends on the coordinated activity of the 1500 or so GnRH
neurons that are present in the hypothalamus, and comprise the GnRH
pulse generator. The operation and control of this essential mechanism
is analyzed in cultured hypothalamic neurons and immortalized GnRH neurons
(GT-1 cells). The latter cells exhibit many of the properties of native
GnRH neurons, including that of intrinsic pulsatility and the ability
to secrete GnRH in an episodic manner in vitro. This process is highly
calcium-dependent and is also influenced by the cyclic AMP system. Much
remains to be learned about the receptor-mediated regulation of the
GnRH neuron, and of its repertoire of plasma-membrane ion channels that
control neuronal excitability. Although the basic mechanism of the GnRH
pulse generator is still incompletely defined, recent findings indicate
that the autocrine regulatory action of GnRH on its receptors expressed
in the GnRH neuron is an important component of this process. The feedback
action of estrogen on the pituitary gland and hypothalamus is also a
major regulator of gonadotropin secretion, and is exerted at the hypothalamic
level through alpha- and beta-estrogen receptors expressed in GnRH neurons
and other cell types. Current studies suggest that the inhibitory action
of estradiol in the GnRH neuron is at least partly mediated by estrogen
receptors expressed in the plasma membrane, rather than those present
in the nucleus.
