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Cell Signaling I Cell Signaling I: Organization of lectures: Sex, Drugs and Violence z General Principles of signaling cascades z Hormone Signaling z Signaling via G-protein coupled receptors: cAMP z Signaling via G-protein coupled receptors: IP3 &DAG Joe W. Ramos [email protected] z Signaling via enzyme-linked receptors www.crch.org/Profiles/jramos z Signal integration z Apoptosis A Metaphor for Cell Signaling: The milkman is the signal. From Genes and the Biology of Cancer, Varmus and Weinberg, 1993 Cell signaling touches all aspects of cell What is signaling? biology: Cell Signaling pathways regulate: A Neutrophil Chasing a Bacterium z the cell cycle- proliferation z the cytoskeleton-migration- z transcription- differentiation z membrane traffic- exocytosis z cell survival and death- apoptosis Courtesy Peter Devreotes z Development- body plan www.hopkinsmedicine.org/cellbio/devreotes Cell signaling is central to modern Forms of Cell Signaling medicine Cancer Diabetes Steroids Adrenaline, Epidermal Estradiol Growth AIDS Factor, NO Cholera Viagra Angina Acetylcholine Delta, FasL Alzheimer’s Whooping cough ….among others 1 Cell matrix proteins may also serve as Same signaling molecule elicits different signals responses in different cells (e) Extracellular matrix-dependent Different Receptor- Target Cells ligand complexes can also activate the SAME response: epinephrin or glucagon can ECM protein (fibronectin) activate glycogen breakdown and release of glucose into the blood. Cell-to-cell communication by extracellular Cells depend on multiple signals signaling usually involves six steps z (1) synthesis of the signaling molecule by the signaling cell z (2) release of the signaling molecule by the signaling cell z (3) transport of the signal to the target cell z (4) detection of the signal by a specific receptor protein z (5) a change in cellular metabolism, function, or development triggered by the receptor-signal complex z (6) removal of the signal, which usually terminates the cellular response An intracellular signaling cascade Phosphorylation Recall: Produced by cellular respiration 15-7 2 Intracellular signaling proteins that Other signaling modifications act as molecular switches z Acetylation, methylation z Ubiquitination, Sumoylation z Proteolysis (caspases) z Second messenger Binding (cAMP, cGMP, DAG, IP3, Ca2+) 15-17 Fast and slow responses to signals Turning off the signal 15-21 Figure from Molecular Biology of the Cell, 4th edn. Signaling Molecules: Hormones 1. Steroids (Estradiol, Testosterone) =cholesterol derivatives 2. Amino acid derivatives (Histamine) (steroids) (Ovary) (Testis) 3. Gases (NO, CO) (Adrenal gland) =tyrosine derivative 4. Peptides and Proteins (Insulin,PDGF) (as is adrenaline) (Thyroid gland) Small hydrophobic molecules: -can diffuse across membrane 15-9 3 Androgen Insensitivity Syndrome Steroid hormone cortisol (AIS) z Some very rare individuals are born as z Cortisol acts on metabolism of proteins, carbohydrates and genetic males but lack the testosterone lipids (androgen) receptor. z Made in Adrenal Gland z They make the hormone, but their cells z Diffuses across PM cannot respond to it. z In blood causes increased z They therefore develop outwardly as females blood pressure and glucose concentrations. z Female genitalia z Gives a quick burst of energy. z However, have non-descended testis However, have non-descended testis z “the Stress Hormone” secreted z No secondary female characteristics (no during fight or flight responses. estrogen!) z Hence, the importance of receptors! 15-10 The nuclear receptor superfamily NO is smooth muscle relaxation -NO diffuses locally, half life is 2-30 seconds -Nerve cell releases acetylcholine which binds endothelial cell. -Relaxation of smooth muscle cells around blood vessels causes the All hormone receptors bind as either heterodimers or homodimers-to simplify things it is vessels to expand increasing blood flow. shown only as a monomer here. 15-11 cGMP mediates local signaling by NO: Cell surface receptor-mediated Viagra and nitroglycerin Viagra and nitroglycerin signaling Acetylcholine is released by the autonomic nerves of the penis. Local blood vessel dilation, Penile erection. z G-Protein Coupled Receptors cGMP can regulate kinases, ion channels, and phosphodiesterases z Enzyme-linked receptors Viagra maintains erection by Nitroglycerin -keeping cGMP levels high relieves Angina -Keeping smooth muscle relaxed Angina is pain resulting from poor Viagra inhibits phosphodiesterase that blood flow to heart normally lowers cyclic GMP levels -nitroglycerine used for 100 years -is converted to NO 4 Three classes of cell-surface A Neutrophil Chasing a chemoattractant receptor The neutrophil is guided by GPCR G protein-coupled receptors and their signaling effectors z Many different mammalian cell-surface receptors are coupled to a trimeric signal-transducing G protein. z Function in: z Light detection z odorant detection z detection of certain hormones and neurotransmitters Demonstration of functional domains in G G-protein-linked receptor protein-coupled receptors: chimeric proteins Ligand 7 Pass Transmembrane proteins 1234567 Light green region binds ligand Orange region binds G-protein G-protein Expressed in Xenopus oocytes See B. Kobilka et al., 1988, Science 240:1310 15-14 5 Clinical relevance 10 minute Break z Half of all known drugs work through G- protein coupled receptors z The genome project has revealed vast numbers of new GPCRs (new drug targets?) G-proteins disassemble into two The G-Protein signaling proteins when activated z Tethered to membrane by •G-proteins are composed of three subunits: α, β, γ Tethered to membrane by hydrophobic lipid anchor z In response to ligand the G-protein is released from the GPCR into two signaling proteins: α subunit and βγ complex z 20 known G-proteins in mammals (different targets) The α subunit switches itself off by A Go protein opens a K+ channel in hydrolyzing its bound GTP the heart muscle The Heart’s contraction is controlled After a few seconds the GTP on by two sets of nerve fibers: one the α subunit is hydrolyzed by speeds and one slows contraction. the intrinsic GTPase activity. To slow, nerves release This inactivates the subunit, acetylcholine. which dissociates from the target Goβγ and re-associates with the βγ Acetylcholine binds a GPCR on heart releasing the G-proteins. complex. Here the Goβγ complex is the active Both the activated α subunit signaling component-binding to the and the βγ complex can K+ channel and thus opening it: less regulate target proteins. frequent contractions. 15-17 6 G-proteins activate enzymes that catalyze G-protein coupled receptors signal the synthesis of messenger molecules by several mechanisms An example enzyme is z We will examine four GPCR second Adenylate cyclase messengers: z cAMP The intracellular message molecules are called z Inositol triphosphate (IP3) Second Messengers z Diacylglycerol (DAG) z Ca+ The signal is thus greatly amplified. z cGMP is also a second messenger 15-18 cAMP increase activates gene Synthesis and degradation of cyclic transcription AMP cAMP activity mediated by G ATP is always present in cells. s cAMP-dependent protein kinase (A kinase or PKA). Adenylate cyclase forms cAMP from ATP by a cyclization reaction that This signaling pathway controls removes two phosphates and joins the many processes in cells remaining phosphate to the sugar. including hormone synthesis. cAMP phosphodiesterase is continually active and breaks the bond to form AMP. cGMP is an analogous second messenger. Earl Sutherland, discovered cAMP 15-22 15-31 Effect of Cholera toxin on Gsα PKA Structure and regulation Cholera toxin is a hexameric protein produced by bacteria: Vibrio cholerae which causes Cholera. cAMP levels 100 fold higher: In epithelial cells this permits massive flow of water from blood into intestines Important tool in early studies of Gs proteins. NAD+=nicotinamide adenine dinucleotide 7 The two branches of the inositol CREB links cAMP signals to transcription phospholipid pathway PKC cAPK=PKA Modification of a common phospholipid precursor Phospholipase C causes an generates several second messengers: increase in intracellular calcium synthesis of DAG and IP3 25 of the known GPCRs activate PLC 2 messengers: -DAG=PKC -IP3=Calcium release Cytosolic Ca2+ levels are tightly Calcium signaling in Rat brain glial controlled cells Ca2+ is actively pumped to the cell exterior and into the ER and mitochondrion. 8 Ca2+ calmodulin structure The Activation of Cam Kinase II Dumbell structure when inactive. Alpha helix “jack-knifes” when Ca2+ bound to surround target protein (CaM Kinase II). CaM Kinase II phosphorylates a wide range of cellular proteins Two major pathways by which G-protein-linked cell- PLC-mediated responses surface receptors generate small intracellular mediators Gq Gs Adenylate cyclase PLC PKA (cAPK) calmodulin Figure from Molecular Biology of the Cell, 3rd edn. Multiple G proteins transduce signals to Turning off GPCRs: arrestin different effector proteins Figure from Molecular Biology of the Cell, 4th edn. Figure from Molecular Biology of the Cell, 4th edn. 9 cAMP-mediated responses 10.
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