Hormonal Secretion Peculiarities - Essay Example

SECRETION INTRODUCTION: Hormonal regulation is usually complex. Complex in the sense that their way of functioning needs deep study to ify underspecific nomenclature. But the ultimate results of their functioning are vivid. Synthesis, secretion, transport, binding to specific receptors and elimination are the steps involved in hormonal regulation. Hormones are derived from other molecules used by the body. Hormones, therefore, can be amino acid derivatives (Thyroxine), modified amino acids (Epinephrine), peptides (ACTH), glycoproteins (Growth Hormone, Luteinizing Hormone), or cholesterol-derived (sex steroids, glucocorticoids, vitamin D). In general, protein-derived hormones bind to cell membrane receptors that transmit the hormonal signal into the cell while cholesterol-derived hormones bind to nuclear receptors that interact either directly with the regulatory portions of genes (promoter) or via other transcription factors to alter gene expression. However there is one exception to this. One class of peptide derived hormone, Thyroxine (T4) and Thyronine (T3), whose structure is based on two tyrosine amino acids fused together exert its effects through binding to nuclear receptors. Hormonal functioning can be viewed in three different styles. They are: - one hormone – many functions; one hormone - specific function and one function – many hormones. The ability of one hormone to exert multiple effects in multiple organs is due to: (1) the extensive distribution of hormones throughout the body via the circulatory system and (2) the presence of different receptors that exhibit differential affinity for the hormone and variable signal transduction properties. Hormone action can be limited to certain tissues because of: (1) the limited distribution of its receptors. For example, ACTH secreted by the anterior pituitary, although it circulates freely in the body, only acts on the adrenal glands because only the adrenal cortex has receptors to ACTH. (2) Circulation of the hormone in a restricted blood supply. For example, CRH is secreted by the hypothalamus into the pituitary venous plexus and acts on the pituitary. Very little CRH can be found circulating in the rest of the body. Hormones act in a concerted fashion to maintain normal function of the organism. Hormone secretion is generally under feed back control mechanism. Integral feed back control mechanism is the characteristic of endocrine system. Hormones and their end products feed back to inhibit or stimulate further secretion of stimulating or inhibitory hormones. Peripheral hormonal levels are maintained and endocrine functioning is heavily regulated by this feed back control mechanism. (Anastassios G. Pittas, 2006) FUNCTIONS OF HORMONES: Many amino acid and peptide hormones are elaborated by neural tissue, with ultimate impact on the entire system. When their composition was still unknown, hypothalamic secretory products were known as releasing factors, since their effect was to release endocrine hormones from the pituitary. More recently the releasing factors have been renamed releasing hormones. Thus, both names are in common use. Releasing hormones are synthesized in neural cell bodies of the hypothalamus and secreted at the axon terminals into the portal hypophyseal circulation, which directly bathes the anterior pituitary. These peptides initiate a cascade of biochemical reactions that culminate in hormone-regulated, whole-body biological end points. Cells of the anterior pituitary, with specific receptors for individual releasing hormones, generally respond through a Ca2+, IP3, PKC-linked pathway that stimulates exocytosis of preexisting vesicles containing the various anterior pituitary hormones. The pituitary hormones are carried via the systemic circulation to target tissues throughout the body. At the target tissues they generate unique biological activities. Hormones on secretion by the endocrine tissues bind to the specific plasma protein carrier, the complex getting disseminated to distant tissues. Carrier proteins for peptide hormones prevent hormone destruction by plasma proteases. Carriers for steroid and thyroid hormones allow these highly hydrophobic substances to be present in the plasma. Tissues having capability of responding to endocrines have two common properties: they posses receptor with very high affinity for hormone and the receptor is coupled to a process that acts on target cells. Activation of these receptors by hormones give way to the production of second messenger called camp. Steroid and thyroid hormones are hydrophobic and diffuse from their binding proteins in the plasma. The resultant complex of steroid and receptor bind to response elements of nuclear DNA, regulating the production of mRNA for specific proteins. Receptors for peptide hormones vary in their structure and style of functioning. Some receptors consist of a single polypeptide chain with a domain on either side of the membrane, connected by a membrane-spanning domain. Some receptors are comprised of a single polypeptide chain that is passed back and forth in serpentine fashion across the membrane, giving multiple intracellular, transmembrane, and extracellular domains. Other receptors are composed of multiple polypeptides. For example, the insulin receptor is a disulfide-linked tetramer with the β subunits spanning the membrane and the α subunits located on the exterior surface. Subsequent to hormone binding, 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). (Michael W. King, 06.11.2006) DAG has two potential signaling roles: (1) it can be further cleaved to release arachidonic acid, which either can act as a messenger or be use in the synthesis of other signaling molecules. (2) Most importantly, DAG activates protein kinase C (C-kinase of PKC), which in turn phosphorylates selected proteins in the target cell. PKC is normally in the cytosol, but it is translocated to the inner layer of the plasma membrane by a mechanism dependent in the rise of intracellular calcium. Once there, Ca2+, DAG, and phosphatidylserine activate the kinase. There are at least 8 PKC isoforms which are particularly abundant in the brain where they modify the excitability of neurons by phosphorylating ion channels. In many cells C-kinase activation leads to increase in the transcription of specific genes. (http://darwin.nmsu.edu/-molbio/mcb520/lecture10.html ) Additionally a series of membrane-associated and intracellular tyrosine kinases phosphorylate specific tyrosine residues on target enzymes and other regulatory proteins. The hormone-binding signal of most, but not all, plasma membrane receptors is transduced to the interior of cells by the binding of receptor-ligand complexes to a series of membrane-localized GDP/GTP binding proteins known as G-proteins. The classic interactions between receptors, G-protein transducer, and membrane-localized adenylate cyclase are illustrated below using the pancreatic hormone glucagon as an example. Signal amplification is an important feature of signal cascades. One hormone molecule leads to formation of many camp molecules and also each catalytic subunit of PKA catalyzes phosphorylation of many proteins during the life time of the camp. When G-proteins bind to receptors, GTP exchanges with GDP bound to the α subunit of the G-protein. The Gα-GTP complex binds adenylate cyclase, activating the enzyme. The activation of adenylate cyclase leads to cAMP production in the cytosol and to the activation of PKA, followed by regulatory phosphorylation of numerous enzymes. Stimulatory G-proteins are designated Gs, inhibitory G-proteins are designated Gi.   (Michael W. King, 06.11.2006) Signal Protein Complexes: -Signal cascades are often mediated by large "solid state" assemblies that may include receptors, effectors, and regulatory proteins, linked together in part by interactions with specialized scaffold proteins. Scaffold proteins often interact also with membrane constituents, elements of the cytoskeleton, and adaptors mediating recruitment into clathrin-coated vesicles. They improve efficiency of signal transfer, facilitate interactions among different signal pathways, and control localization of signal proteins within a cell. Signal complexes are often associated with lipid raft domains of the plasma membrane. Scaffold proteins as well as signal proteins may be recruited from the cytosol to such membrane domains in part by insertion of lipid anchors, or by interaction of pleckstrin homology or other lipid-binding domains with head-groups of transiently formed phosphatidylinositol derivatives, , such as PIP2 or PI-3-P. (www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/signals.htm ) MULTIFARIOUS ACTIONS OF HORMONES: Projectaware.org cites the results of a study reported in the Journal of the American College of Cardiology (April 2003) in which it is laid that a form of oral estrogen, increases C-reactive protein (CRP) in the blood, while an estrogen skin patch, does not. CRP is a marker of inflammation in the blood that has been found to be a heart disease risk factor. The study confirms earlier research showing that transdermal estrogen does not raise CRP levels in the blood, while estrogen pills do. Transdermal estrogen and oral estrogen have differing effects on androgens in the body. Oral estrogen lowers free testosterone and can lead to androgen deficiency affecting libido among other things, while transdermal estrogen has little effect on testosterone levels. Transdermal estrogen may offer other advantages over oral estrogens. However more research is needed in this regard. (Project AWARE, 06.11.2006) PROLACTIN AND ITS DEVIATED CHARECTERISTICS: Contrary to other pituitary hormones, the hypothalamus suppresses the secretion of Prolactin from pituitary. Prolactin usually secretes only on the release of hypothalamic brake on the lactotroph. This obviously is in contrast with all other pituitary hormones that excitingly fall due to loss of hypothalamic releasing hormones. Dopamaine plays a key role in inhibiting the secretion of prolactin by binding to the receptors on lactotrophs. However, GnRH, thyroid releasing hormones and vasoactive intestinal peptides regulate the secretion of prolactin in a positive way. (R.Bowen,2002, ). NEGATIVE FEED BACK MECHANISM IN GROWTH HORMONES: The activities of growth hormones comprise both direct effect and indirect effect. In direct effect, the fat cells are broken down to triglyceride and their accumulation is suppressed. In indirect effect, insulin like growth factor-I (IGF-I) acts directly on target cells. Growth hormones too function under negative feed back mechanism. GHRH, a hypothalamic peptide and Ghrelin, a stomach originating peptide stimulate both synthesis and secretion of growth hormones, whereas Somotostatin, a peptide produced in hypothalamus and other tissues, inhibits the release of growth hormones. High blood levels of IGF-I stimulate release of the Somotostatin and results in inhibition of the release of growth hormones. Such inhibition occurs in response to the release of GHRH and other stimulators like low blood glucose concentration. (R.Bowen,2002). During target-cell adaptation β-arrestin blocks the ability of receptorto activate Gs. (http://darwin.nmsu.edu/-molbio/mcb520/lecture10.html). FUNCTIONING OF INSULIN: The functioning of insulin is quite interesting to study. The interaction between insulin and its protein receptor located on the cell membranes alone activate the target cells. The structure of receptor proteins explains its functioning style and subsequent loss of protein in the target cells. The receptor protein consists of four poly peptide chains to form a cylinder structure. Binding of insulin transforms this shape into a tunnel shape through which molecules like glucose enter. Loss of receptor protein is mainly ascribed to its small amount, which is bound to decrease in amount during the attempts of extracting the receptor complex from the membrane. The progressive increase in blood glucose level increases insulin level and finally all insulin receptors get removed from the surface of the cell. (http://www-biol.paisley.ac.uk/courses/stfunmac/glossary/receptor.html ) CONCLUSION: Dr. Deborah Mowshowitz, (2006) of Columbia University has tried to explain these multifaceted actions of hormones. He ascribes three reasons for one hormone – many functions: - 1. Presence of different hormone receptors in different tissues causing more than one signal. 2. Difference in combination of TF’s in each cell, as more than one TF is required to get proper transcription of each gene. 3. DNA being the same in all cells. This third factor gives rise to the following outcomes: a) Excepting the immune system all cells have the same cis acting regulatory sites, the same HREs and enhancers. b) The cis acting regulatory sites remaining constant, the trans acting factors and hormones vary. c) All cells have the same genes for TFs, and receptors but different ones are made in different cells. The Transmembrane Receptors work well using G- Proteins. The role of G – Proteins in signal transduction is typical. It covers two stages namely, activation and inactivation. During activation exchange takes place as follows: Protein – GDP(inactive) + GTP ---- Protein – GTP (active) + GDP Hydrolysis takes place in the phase of inactivation; Protein – GTP(active) ----- Protein – GDP (inactive) + phosphate. .( Dr. Deborah Mowshowitz,2006) To present this state in a concise manner one can say that what any hormone does depends on combination of proteins already in the target cells *** **** ******** Reference list-- (Anastassio G. Pittas, 2006, Tufts OpenCourseWare @ http://ocw.tufts.edu/Content/14/Lecturenotes/265876, retrieved on 06.11.2006) (R.Bowen,2002, “Prolactin” @ www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/prolactin.html ) (Dr. Deborah Mowshowitz, (2006) @ www.columbia.edu/cu/biology/courses/c2006/lectures06/lect.12.06.html ) (Michael W. King, 2006, “Structure and Functions of Hormones”, @ http://web.indstate.edu/thcme/mwking/peptide-hormones.html retrieved on 06.11.2006) (Michael W. King, 2006, “Structure and Functions of Hormones”, @ http://web.indstate.edu/thcme/mwking/peptide-hormones.html retrieved on 06.11.2006) (Project AWARE, “About Estrogen”, @ http://www.project-aware.org/Managing/Hrt/estrogen.shtml retrieved on 06.11.2006) (http://www-biol.paisley.ac.uk/courses/stfunmac/glossary/receptor.html) (http://darwin.nmsu.edu/-molbio/mcb520/lecture10.html ) (www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/signals.htm ) Read More