Hormones and Signal Transduction PDF

Lippincott’s illustrated reviews Chapter 44, Page 520 Lectures 6 Hormones and Signal Transduction 1  Specific Objectives By the end of this lecture students can be able to: Understand the meaning of signal transduction. Differentiate betw...

Lippincott’s illustrated reviews Chapter 44, Page 520 Lectures 6 Hormones and Signal Transduction 1  Specific Objectives By the end of this lecture students can be able to: Understand the meaning of signal transduction. Differentiate between the signal transduction of different hormones. 2  Introduction The nervous system and endocrine system are the major control mechanisms that integrate the functions of the tissues in the body. The nervous system transmits electrochemical sign also between the brain and peripheral tissues for coordinating the diverse body functions. The endocrine system releases chemical mediators or hormones into the circulation. 3  The classical definition of a hormone is “substances released from ductless or endocrine glands directly to the blood”. to gland gray A more modern definition of a hormone is that it is synthesized by one type of cells and transported through blood to act on another type of cells. Based on mechanism of action the hormones may be classified into two classes: I. Hormones with cell surface receptors II. Hormones with intracellular receptors 4  x 5 Group Mechanism of action Examples of hormone 1A Hormones bind with cell surface ACTH, ADH, FSH, HCG, LH, TSH receptors with cAMP as the second MSH, PTH, CRH, Glucagon, Calcitonin messenger Catecholamine, Retinoic acid 1B Hormones having cell surface receptors; ANF (atrial natriuretic factor), cGMP as second messenger NO (nitric oxide) 1C Hormones having cell surface receptors; TRH, GnRH , Catecholamines, second messenger is calcium or Acetylcholine CCK, Gastrin, Vasopressin, Phosphatidyl inositol (PIP2) Oxytocin, PDGF 1D Hormones having cell surface receptors Insulin, Somatomedin, EGF, FGF, PDGF, and mediated through tyrosine kinase CGSF, NGF, IGF 1E Hormones having cell surface receptors, IL, GH, PRL, TNF, Adiponectin, Leptin, but intracellular messenger is a kinase or Resistin, Erythropoietin utilize phosphatase cascade 1I Hormones that bind to intracellular Glucocorticoids, Mineralocorticoids, receptors Estrogens, Progesterone, Androgens, Calcitriol, Thyroxine 6  Mechanism of action of hormones A- Hormones with extracellular Receptors 1. Hormones Acting through Cyclic AMP (cAMP) as a second messenger 7 8 A. Activation of G-Protein Each hormone has specific receptor on the membrane. When the hormone receptor complex is formed, the activated receptor stimulates the G protein (GTP binding regulatory proteins) to become active. 9 B. G-Protein Activates Adenyl Cyclase came Active G-protein carries the excitation signal to adenylate cyclase which embedded in the plasma membrane. The hormone is not passed through the membrane; but only the signal is passed; hence this mechanism is called signal transduction. Signal transduction in this case is through G protein. 10 C. Formation of cyclic AMP (cAMP) Adenyl cyclase or adenylate cyclase (AC) converts ATP to cAMP (3',5'-cyclic AMP), After finishing the action cAMP can be hydrolyzed to 5' AMP by phosphodiesterase (PDE). Regulation D. Second Messenger Activates protein kinase (PK) The cAMP (second messenger), in turn, activates the enzyme, PKA (Cyclic AMP dependent protein kinase). 11 E. Protein kinase Phosphorylates the Enzymes Phosphorylation usually takes place by transfers a phosphate group from ATP to OH groups of serine, threonin or tyrosine residues of the substrates. The enzymes may be activated or inactivated by this phosphorylation. This is an example of covalent modification. More than thousand protein kinases are now known. Each of the activated protein kinases has specific metabolic roles. 12  cAMP also has a long lasting effect on gene expression The translocation of the active PKA subunits to the nucleus induces phosphorylation of cAMP regulated gene regulatory proteins or CREBs. These proteins will bind to cAMP sensitive regulatory elements (CRE) on genes, thus controlling their expression to produce specific proteins. 13 14  2. Hormones Acting through Cyclic GMP (cGMP) Cyclic GMP is another important second messenger involves in contractile function of smooth muscles, visual signal transduction (rhodopsin cycle or visual cycle) and maintenance of blood volume. It is formed from GTP by the action of guanyl cyclase. Cyclic GMP activates cGMP-dependent protein kinase G (PKG), which phosphorylates important effector proteins 15  9 16  3. Hormones Acting through Calcium ions Calcium is an important intracellular regulator (although it is extracellular cation) of cell function like contraction of muscles, secretion of hormones and neurotransmitters, cell division and regulation of gene. Intracellular calcium acts as a mediator of hormone action either independently or in conjunction with cAMP. 17  Calmodulin (calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Active calmodulin will activate another functional proteins or enzymes as: Adenyl cyclase calcium-dependent protein kinases calcium-magnesium-ATPase 18 19  B- Hormones with Intracellular Receptors The hormones in this group include the steroid hormones and thyroid hormones. They diffuse through the plasma membrane and bind to the receptors in the cytoplasm. The hormone receptor (HR) complex is formed in the cytoplasm. The complex is then translocated to the nucleus. 20 21  In the nucleus, the HR binds to the hormone response elements (HRE) or steroid response elements (SRE). The SRE acts as an enhancer element and when stimulated by the hormone, would increase the transcriptional activity. The newly formed mRNA is translated to specific protein, which brings about the metabolic effects. Best examples of the effect of hormones on genes are: a. The induction of synthesis of aminotransferases by glucocorticoids. b. Synthesis of calcium binding protein by calcitriol. Active form of vitamin D 22 Reference Book: Vasudevan, D. M., Sreekumari, S., and Kannan, V.., 2011. Textbook of biochemistry for medical students, 6th Edition. 23