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Lecture 9

Lecture 9.doc

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Biology 2382B

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Lecture 9: Basic Principles of Cell Signalling and GPCR System Signal Transduction - Conversion of one signal into another - Involves growth factors, cytokines, hormones, ECM, neurotransmitters, light, sound etc. - Incredibly “hot” area; over 300000 papers published - All aspects of normal development & physiology - Initiator of diseases – “cancer, heart, diabetes” – turned on too much - Some of the players: Receptor Tyrosine Kinases (RTK’s), G-protein couples receptors (GPCR’s), Proto-oncogenes (Ras), Mitogen Activated Protein Kinases (MAPK) Basic Elements of Cell Signalling Signal or signalling molecule (ligand, primary messenger) - Small molecules (epinephrine, acetylcholine, steroids), peptides, hormones etc. - Large molecules, growth factors, cytokines (proteins) Intracellular signalling and effector proteins - G Proteins, protein kinases and phosphates, etc Second messengers - Ca++, cAMP, cGMP, IP3, DAG, NO, etc Receptors - cell surface receptors - intracellular receptors The second major group of extracellular signals, the small, lipid soluble hormones, including many different steroid hormones, retinoids, and thyroid hormones – that can diffuse through plasma and nuclear membranes and interact directly with the transcription factors that they control. The intracellular receptor for most of these lipid-soluble hormones, which constitute the nuclear receptor super-family, function as transcription activators when bound to their ligands. Nuclear Receptors - all the nuclear receptors have a unique N terminal region of a variable length (100-500 amino acids) - Portions of this variable region function as activation domains in some nuclear receptors - The DNA binding domain maps near the center of the primary sequence and has a repeat of the C4 zinc-finger motif - The hormone binding domain, located near the C terminal region contains a hormone dependant activation domain - In some nuclear receptors the hormone binding domain functions as a repression domain in the absence of ligand - ER, PR & GR are in the cytoplasm - TR & RAR are in the nucleus Nuclear Receptor Response Elements: Hormones - Response Elements: bind several nuclear receptors - Heterodimeric nuclear receptors are located exclusively in the nucleus. In thte absence of their hormone ligand, they repress transcription when bound to their cognate sites in DNA, they do so by directing hsitone deacetylation - In ligand – bound conformation, heterodimeric nuclear receptors containing RXR can direct hyperacetylation of histones in nearby nucleosomes - In the presence of ligand, ligand binding domains of nuclear receptors also bind to a mediator, stimulating preinitiation complex assembly - Homodimeric receptors are found in the cytoplasm in the absence of their ligands. Hormone binding to these receptors leads to translocation in the nucleus. The hormone dependant translocation of the homodimeric glucocorticoid receptor (GR) was demonstrated in the transfection experiments: fusion proteins from expression vectors demonstrate that the hormone binding domain of the GR mediates translocation to the nucleus in the presence of the hormone - When the GR isn’t bound to a hormone it is anchored in the cytoplasm as a large protein aggregate complexed with inhibitor proteins; as long as the receptor is confined to the cytoplasm it can’t interact with target genes - Hormone binding of homodimeric receptors releases the inhibitor proteins to allow the receptor to enter the nucleus where it activates transcription - The characteristic nucleotide sequences of the DNA sites that bind nuclear receptors are called response elements. - In the absence of hormone, the receptor in trapped in the cytoplasm by inhibitor proteins (e.g. HSP90). - Hormone binding to a nuclear receptor releases the inhibitor protein, allowing the receptor to enter the nucleus. - The receptor binds to a response element of the target gene and stimulate preinitiation complex assembly required for transcription (mRNA synthesis). - Glucocorticoid is a potent anti-iflammatory and immunosupressive reagent, also many other functions From Extracellular Signal to Cellular Response - Communication by extracellular signals usually involves the following steps: Synthesis of the signalling molecule by the signalling cell and its incorporation into small intracellular vesicles (1), its release into the extracellular space by exocytosis (2), and transport of the signal to the target cell (3) where the signalling molecule binds to a specific cell-surface receptor protein leading to activation of a receptor (4). The activated receptor then initiates one or more intracellular signal transduction pathways (5) leading to specific changes, usually short term, in cellular function, metabolism, or movement (6a) or long term changes in gene expression or development (6b). Termination of the cellular response is caused by intracellular signalling molecules that inhibit receptor function (7) and by removal of the extracellular signal (8). - The overall process of converting extracellular signals into intracellular responses, as well as the individual steps in this process, is termed signal transduction. Termination of the cellular response is caused by intracellular signaling molecules that inhibit receptor function and by removal of the extracellular signal. Short-term cellular responses are associated with changes in the activity and functions of specific enzymes and other proteins that pre-exist in the cell. Long- term cellular responses are associated with changes in the amounts of specific proteins produced by a cell, most commonly by modification of transcription factors that stimulate or repress gene expression. Primary Receptors Secondary Receptors - the most numerous class of receptors in humans are GPCRs (G protein coupled receptors) – receptors in the visual, smell, taste systems, many neurotransmitter receptors, and most of the receptors for hormones that control carbohydrate, amino acid and fat metabolism The Four Forms of Intercellular Signalling - The signalling molecules are synthesized and secreted by signalling cells (endocrine cells), transported through the circulatory system of the organism, and finally act on target cells distant from their site of synthesis. The term hormone generally refers to signalling molecules that mediate endocrine systems - The signalling molecules released by a cell affect only those target cells in close proximity. The conduction by a neurotransmitter of a signal from one nerve cell to another or form a nerve cell to a muscle cell (inducing or inhibiting muscle contractions) - Autocrine signalling cells respond to substances that they themselves release. Some growth factors stimulate their own growth and proliferation. This is often characteristic of tumour cells - Signalling molecules that are integral membrane proteins located on the cell surface also play an important role in development. In some cases, such membrane bound signals on one cell bind to the receptors of adjacent cells to trigger differentiation. In other cases, proteoly
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