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Endocrinology

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Published in: Biology
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Endocrinology

Subhamoy M / Kolkata

10 years of teaching experience

Qualification: M.Sc (Presidency College - 2011), B.Sc (Surendranath College - 2009), B.Ed (WBUTTEPA - 2019)

Teaches: Biology, Botany, Physiology, Zoology, Bio-medical, Food & Nutrition, Medical Entrance Exams, NEET

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  1. Signal Transduction Signal transduction at the cellular level refers to the movement of signals from outside the cell to inside. Examples are: Threat -5 epinephrine (adrenaline) released from adrenal glands -5 binds to B-Adrenergic receptor of another cell energy stores are mobilized and cardiac function is improved Intake of full meal insulin released from B-cells of Pancreas -5 binds to Insulin receptor -5 increased glucose uptake Wound Epidermal growth factor (EGF) released -5 stimulates specific cells to grow and divide i.e. assists in expression of growth-promoting genes In each case, the cell receives information that a certain molecule within its environment is present more than its normal concentration (i.e. greater than its threshold concentration) and the chain of events which converts this information into the final physiological response is known as signal transfuction. The signal molecule (i.e. adrenaline, insulin or EGF) is known as the "primary messenger" or the "ligand". Signal transduction systems allow information to control cellular processes such as: Gene expression. Change in enzyme activity. Growth. Responses to stress. Death. Developmental changes. Adaptations. Locomotion. Signalling Molecules: Examples of signal molecules: Hormones. Growth factors. Extracellular matrix components e.g. fibronectin. Cytokines. Neurotransmitters e.g. acetylcholine. Basic Principles of Signal Transduction The coordination of metabolism in the separate organs of mammals is achieved by hormonal and neural signaling. Individual cells in one tissue sense a change in the organism's circumstances and respond by secreting extracellular chemical messenger. Endocrine cells secrete hormones, neural cells secrete neurotransmitters. In each case, the extracellular messenger passes to another cell where it binds to a specific receptor molecule and triggers a change in the activity of the second cell.
  2. In neural signaling, the chemical messenger (neurotransmitter e.g. acetylcholine) may travel only a fraction of micrometer across the synaptic cleft to the next neuron in a chain. In contrast hormones are carried rapidly in the blood between distant organs and tissues; they may travel a meter or more before encountering their target cell. During signal transduction: the number of proteins and other molecules participating in these events increases as the process goes from the initial stimulus, resulting in a signal cascade, eliciting a large response Elements of a signal transduction System Sender Signal Nondestructive Medium Selective Receiver Transducer Amplifier Effector Response Principles of Signal Transduction Environmental (Primary messenger) Cell surface receptor Signal Reception (Secondary messenger) Amplification Feedback pathways Regulate the entire signal process. Other chemical forms (Multi-step) Cellular effectors Signal-transduction pathway: Transduction Response(s) Signal transduction pathways allow cells to respond to environmental signals. 1. Release of primary messenger: a stimulus (wound/digested meal etc.) triggers release of signal molecule. 2. Reception of primary messenger: Transmembrane receptors on cell membrane (with half of the receptor outside the cell and the other half inside the cell) recognize and bind the primary messenger (or the ligand). The primary messenger binds to the extracellular half of the receptor, which changes its tertiary or quaternary shape and conveys another signal (second messenger) inside the cell.
  3. 3. 4. 5. Delivery of message inside the cell by the second messenger: small molecules called second messengers relay signals received at receptors on the cell surface such as arrival of protein hormones, growth factors etc. — to target molecules in the cytosol and/or nucleus. These are intracellular molecules that change in concentration in response to environmental signals (i.e. primary messenger). Examples: cyclic AMP and cyclic GMP, calcium ion, inositol 1,4,5-triphosphate (IP2) and diacylglycerol (DAG). Second messengers have the following properties: a. b. c. The second messengers serve to greatly amplify the strength of the signal. Binding of a ligand to a single receptor at the cell surface may end up causing massive changes in the biochemical activities within the cell. i.e. a low concentration of signal in the environment, even as little as a single molecule, can yield a large intracellular signal (i.e. large number of second messengers) and large response They are often free to diffuse to other cellular compartments where they cal influence processes throughout the cell Second messengers in multiple signaling pathways can cause problems. Cross- talk (i.e. input from several signaling pathways at one time rather than signal from individual independent pathways) may alter the concentration of a common second messenger. Cross-talk can either enhance the activity of the cell or cause the changes in second-messenger concentration to be misinterpreted Activation of effectors that directly alter physiological response: the ultimate effect of the signal pathway is to activate/inhibit pumps, enzymes and gene-transcription factors that directly control metabolic pathways, gene activation and processes such as nerve transmission Termination of the signal: after the response has been achieved, the signal must be terminated or else the cell will lose its responsiveness to new signals. If not terminated, signal-transduction processes can cause many cancers (especially processes that control cell growth). One mechanism for termination is by: Protein phosphatases, which are enzymes that hydrolytically remove specific phosphoryl groups from modified proteins. Mechanism of second messenger production (i.e. Step 2 and 3 of signal-transduction pathway): Hydrophilic messengers cannot cross the cell membrane. This restriction forces them into a 'classical' method of messenger action, namely the production of intracellular second messengers which are responsible for the effects of the various messengers. Ligand binds to receptors located on the external surface of the plasma membrane. The resultant ligand•receptor complex is coupled to an enzyme located on the internal surface of the cell membrane and stimulates the conversion of some metabolite into a second messenger. This second messenger then is responsible for the manifestations of all of the effects of the primary messenger inside the cell In a large number of cases, the second messenger acts by stimulating or inhibiting protein phosphorylation/ dephosphorylation cascades. Cascades have certain advantages to include signal divergence, convergence and amplification.
  4. Two Features of transduction that alter protein shape and function: Allosteric changes Phosphorylation Many second messengers elicit responses by activating protein kinases: these small molecules bind and activate protein kinases, ion channels, and other proteins, to continue the signaling cascade. These enzymes transfer the terminal phosphate of ATP to specific serine, threonine, or tyrosine residues in proteins. OH (Ser, Thr, Tyr-) Frc•te i kinas e ATP (Ser, T yo Protein phosphatases ADP Are enzymes that hydrolytically remove specific phosphoryl groups from modified proteins. They are one mechanism for the termination of a signaling process. Without such termination, cells lose their responsiveness to new signals. Signaling processes that fail to be terminated properly may lead to uncontrolled cell growth and the possibility of cancer. Types of receptors I- Cell-surface receptors II- Internal receptors Cell-surface receptors: Most signal molecules are too large and too polar to pass through the membrane, and no appropriate transport systems are present. The information that signal molecules are present must be transmitted across the cell membrane without the molecules themselves entering the cell. A membrane associated receptor protein often performs the function of information transfer across the membrane. Cell-surface receptors may be: 1- Integral transmembrane receptors .Recognize the vast majority of extracellular signaling molecules Usually for proteins and charged molecules
  5. They give rapid response, seconds - minutes Example; receptors for epinephrine and growth hormone. 2- Transmembrane receptors: span the plasma membrane of the cell, with one part of the receptor on the outside of the cell (extracellular domain) and the other on the inside of the cell (intracellular origin). Cell-surface receptors Allow the activation of signal transduction pathways in response to the activation by the binding molecule or ligand The ligand itself does not pass through the plasma membrane E.g.: seven-transmembrane-helix receptors (7 TM receptors), they change conformation in response to ligand-binding and activate G-proteins Transmembrane receptors E=extracellular space P=plasma membrane l=intracellular space Biological functions mediated by 7 TM receptors Smell Taste Vision Neurotransmission Hormone secretion Chemotaxis Exocytosis Control of blood pressure Embryogenesis Cell growth and differentiation Development Viral infection Carcinogenesis About 7 TM receptors: They are the largest class of cell-surface receptors B-adrenergic receptor (B -AR, for epinephrine) is of this class
  6. Members of this family are responsible for transmitting information initiated by signals as diverse as hormones, neurotransmitters, odorants, tastants and even photons Approximately 50% of therapeutic drugs use target receptors of this class These receptors contain seven helices that span the membrane bilayer They are sometimes referred to as serpentine receptors First member of this family to have its 3D structure determined was rhodopsin, which plays an essential role in vision Binding of a ligand like epinephrine fron outside the cell to a 7 TM receptor like B-AR induces a conformational change in the part of the 7 TM receptor that is positioned inside the cell This conformational change in the receptor's cytoplasmic domain activates a protein called a G-protein because it binds guanyl nucleotides. The activated G protein stimulates the activity of adenylate cyclase, an enzyme that increases the concentration of cAMP by forming it from ATP. The G protein and adenylate cyclase remain attached to the membrane, whereas cAMP can travel throughout the cell carrying the signal originally brought by the binding of the ligand (in this case, epinephrine) There are many different classes of transmembrane receptors that recognize many different extracellular signaling molecules, examples: G-protein coupled receptors Receptor tyrosine kinase G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are heterotrimers (i.e., made of three different subunits) associated with the inner surface of the plasma membrane and transmembrane receptors of hormones, etc. These are 7 TM receptors called G protein- coupled receptors (GPCRs) because they signal through G-proteins The three subunits are: Gu, which carries the binding site for the nucleotide. At least 20 different kinds of Gu molecules are found in mammalian cells (this subunit binds the guanyl nucleotide i.e. either GDP or GTP. It is a member of P-loop NT Pase family and P-loop participates in nucleotide binding) The u and y subunits are anchored to the membrane by covalently attached fatty acids. The role of the hormone-bound receptor is to catalyze the exchange of GTP for bound GDP. How They Work: • In the inactive state, Gu has GDP in its binding site. When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes). This triggers an allosteric change in Gu causing GDP to leave and be replaced by GTP. GTP activates Gu causing it to dissociate from GßGy (which remain linked as a dimer).
  7. Activated Gu in turn activates an effector molecule. In a common example, the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP) Activated Gu is a GTPase so it quickly converts its GTP to GDP. This conversion, coupled with the return of the Gß and Gy subunits, restores the G protein to its inactive state. (G proteins transmit a signal when bound to GTP and they are silent when bound to GDP) The dissociation of the G-protein heterotrimer into Gu and Gßy units transmits the signal that the receptor has bound its ligand. A single hormone-receptor complex can stimulate nucleotide exchange in many G-protein heterotrimers. Thus, hundreds of Gu molecules are converted from their GDP into their GTP forms per each bound molecule of hormone, giving an amplified response.

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