SOMATOSTATIN--REGULATION OF CELLULAR SIGNALING

Project: Research project

Description

Tissue-specific proteolytic cleavage of prosomatostatin generates two
biologically active peptides, somatostatin-14 (SS-14) and somatostatin-
28 (SS-28). These two peptides are thought to activate distinct
receptors in the brain, pituitary, pancreas, and GI tract. Because
somatostatin regulates the functions of so many target tissues,
unraveling the complexities of somatostatinergic signaling is a major
problem in neuroendocrinology. We, and others, have recently identified and isolated cDNAs encoding two
distinct somatostatin receptors: SSR1 and SSR2. These cDNAs provide
the best evidence for the existence of distinct functional subtypes of
somatostatin receptors and additionally supply the means to determine
the physiological significance of this receptor multiplicity. One of
the goals of this proposal is to determine whether these receptor
subtypes display different affinities for SS-14 and SS-28. Both somatostatin peptides elicit relatively complex biological
responses, by activating or inhibiting multiple signal transduction
pathways. For example, alterations in adenylyl cyclase activity,
potassium efflux, and calcium influx all contribute to the ability of
SS-14 to inhibit prolactin secretion from pituitary cells. A second
goal of this proposal is to determine whether these different biological
actions of somatostatin are mediated by distinct receptor subtypes and
G protein signaling pathways. Perhaps the most unique action of somatostatin is its ability to inhibit
tumor cell growth. This antineoplastic action of somatostatin may be
mediated through its stimulation of a protein tyrosine phosphatase. We
have identified a novel G protein pathway used by somatostatin to
stimulate a protein tyrosine phosphatase (PTP) activity in human tumor
cells. Our third goal is to characterize the components of the pathway
that mediate this effect. In conclusion, somatostatin participates in a unique signaling system
capable of activating at least four separate G protein-coupled pathways.
Prosomatostatin and the family of somatostatin receptors and effectors
can serve as a paradigm for how a single neuropeptide system mediates a
wide variety of biological effects. Through the coordinated expression
of specific ligands, receptors, G proteins, and effectors somatostatin
is able to increase the range and scope of its actions. The specificity
of the interactions between ligands, receptors, G proteins and effectors
governs the signaling pathway utilized in the cell. We have isolated
the necessary reagents and have developed the technical tools to begin
to understand the molecular rules that govern the interactions.
Understanding these rules will facilitate the development of therapeutic
strategies designed to discriminate among the many effects of
somatostatin.
StatusFinished
Effective start/end date9/30/929/29/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Somatostatin
GTP-Binding Proteins
Somatostatin-28
Somatostatin Receptors
Protein Tyrosine Phosphatases
Peptides
Complementary DNA
Neuroendocrinology
Lactotrophs
Ligands
Neuropeptides
Adenylyl Cyclases
Human Activities
Antineoplastic Agents
Gastrointestinal Tract
Pancreas
Potassium
Calcium
Brain
Growth

ASJC

  • Medicine(all)