Definition
Signal transduction is a process in which a peptide transfers specific information from the outside of the target cell to exert a cellular response.
Discovery
Rensing L in 1972 described, Periodic geophysical and biological signals as exogenous inducers in animal organisms 1. Tonndorf J in 1975 explained signal transmission in the cochlear hair cell-nerve junction 2. Landmark discoveries in the field of signal transduction were made by Rodbell in 1980 where he described the role of hormone receptors and GTP-regulatory proteins in membrane transduction 3. Further discoveries provided new and provocative insight toward identifying potentially physiologically relevant steroid receptors capable of mediating nongenomic signaling, describing a novel family of high-affinity membrane steroid receptors with structure and signaling similar to GPCRs 4.
Structural Characteristics
Most signal transduction involves the binding of extracellular signaling molecules to cell-surface receptors and subsequently trigger events inside the cell. Peptide molecules involved in signal transduction functions as, hormones, growth factors, cytokines, neurotrophins etc 5,6,7. The glycoprotein signal transduction molecules are the most chemically complex family of the peptide hormones. Each of the glycoprotein hormones is an (a:ß) heterodimer, with the a-subunit being identical in all members of the family. The biological activity of the hormone is determined by the ß-subunit, which is not active in the absence of the a-subunit. The molecular weight of the gonadotropins (follicle stimulating hormone, FSH; luteinizing hormone, LH, and human chorionic gonadotropin, hCG) is about 25,000 Daltons, whereas that of the thyroid tropic hormone, thyroid stimulating hormone (TSH) is about 30,000. All members of the glycoprotein family transduce their intracellular effects via their respective receptors and the associated G-protein, adenylate cyclase, second-messenger systems. Adrenocorticotropic hormone is a 39 amino acid peptide derived by post-translational modification from a 241 amino acid precursor known as pro-opiomelanocortin (POMC). Glucagon is a 29-amino acid hormone synthesized by the a-cells of the islets of Langerhans as a very much larger proglucagon molecule. Novel Neurotrophin-1 (NNT-1) is found predominantly in lymph nodes and spleen, which contains 225 amino acids with a molecular mass of 22 kDa in its mature form.
Mode of Action
Upon binding of signaling peptides to the cell surface receptor, a signal is transduced to the interior of the cell, where second messengers and phosphorylated proteins generate appropriate metabolic responses. The main second messengers are cAMP, Ca2+, inositol triphosphate (IP3), and diacylglycerol (DAG). Proteins are phosphorylated on serine and threonine by cAMP-dependent protein kinase (PKA) and DAG-activated protein kinase C (PKC). Additionally a series of membrane-associated and intracellular tyrosine kinases phosphorylate specific tyrosine residues on target enzymes and other regulatory proteins. A second class of peptide induces the transduction of 2 second messengers, DAG and IP3. Hormone binding is followed by interaction with a stimulatory G-protein which is followed in turn by G-protein activation of membrane-localized phospholipase C-?, (PLC-?). PLC-? hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce 2 messengers: IP3, which is soluble in the cytosol, and DAG, which remains in the membrane phase. Cytosolic IP3 binds to sites on the endoplasmic reticulum, opening Ca2+ channels and allowing stored Ca2+ to flood the cytosol. There it activates numerous enzymes, many by activating their calmodulin or calmodulin-like subunits. DAG has 2 roles: it binds and activates protein kinase C (PKC), and it opens Ca2+ channels in the plasma membrane, reinforcing the effect of IP3. Like PKA, PKC phosphorylates serine and threonine residues of many proteins, thus modulating their catalytic activity 8,9.
Functions
The normal function of a cell depends upon an intact signal regulation/termination system. If this system malfunctions, the host may experience pathophysiological consequences such as abnormal secretion, motility, growth, or even the development of cancer 3,8,9.
Glucose metabolism, the activated glycogen phosphorylase degrades carbohydrate stored as glycogen in the fat body cells. The glycolytic products of glycogen degradation serve as precursors for the synthesis of trehalose, the major insect blood sugar 10.
Lipogenesis, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the IGFs and relaxin.
Gluconeogenesis, Glucagon also binds to receptors in adipose tissue resulting in increased activation of hormone-sensitive lipase (HSL). In the liver the oxidation of fatty acids is necessary to provide the energy needed for gluconeogenesis which is activated in liver in response to glucagon.
In gut, there are more than 30 peptides currently identified as being expressed within the digestive tract, making the gut the largest endocrine organ in the body.
Cytokines, are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication.
References
1. Rensing L (1972). Periodic geophysical and biological signals as Zeitgeber and exogenous inducers in animal organisms. Int. J. Biometeorol., 16:113-125.
2. Tonndorf J (1975). Davis-1961 revisited. Signal transmission in the cochlear hair cell-nerve junction. Arch. Otolaryngol., 101(9):528–535.
3. Rodbell M (1980). The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature, 284 (5751)17–22.
4. Hammes SR (2003). The further redefining of steroid-mediated signaling. PNAS., 100 (5):21680–2170.
5. Sugden D, Davidson K, Hough KA, Teh MT (2004). Melatonin, melatonin receptors and melanophores: a moving story. Pigment Cell Res., 17 (5): 454–460.
6. Carpenter G, Cohen S. (1990). Epidermal growth factor. J. Biol. Chem., 265(14): 7709–7712.
7. Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004). Interferon-? an overview of signals, mechanisms and functions. Journal of Leukocyte Biology, 75: 163-189.
8. Lalli E, Sassone-Corsi P (1994). Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem., 269 (26):17359–17362.
9. Rosen O (1987). After insulin binds. Science, 237(4821):1452–1458.