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Second Messengers and Signal Transduction

Second Messengers and Signal Transduction. Tim Bloom, Ph.D. 104A Hall of Science 893-1712. Overview. Signal transduction- a concept Second messengers Characteristics Examples Benefits. Signal Transduction. Intra cellular communication Detection of extracellular event

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Second Messengers and Signal Transduction

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  1. Second Messengers and Signal Transduction Tim Bloom, Ph.D. 104A Hall of Science 893-1712

  2. Overview • Signal transduction- a concept • Second messengers • Characteristics • Examples • Benefits

  3. Signal Transduction • Intracellular communication • Detection of extracellular event • Generation of internal change • Bottom line- presence of external ligand causes a change inside cell

  4. Ligands Estrogen Acetylcholine Insulin Epinephrine Receptors Transcription factor Sodium channel Receptor kinase G protein-coupled receptor Signaling Examples

  5. Second Messengers • Molecules whose presence is a signal • Synthesized or released from storage • Act as intracellular ligands • Commonly used in G protein-coupled receptor signaling • Made or released by effector proteins • (Ligand for GPCR is 1st messenger)

  6. Second Messengers • General characteristics • Low amounts in resting state • Regulated synthesis • Regulated destruction • Act through other proteins

  7. Second Messengers • Cyclic nucleotides • cAMP • cGMP • Calcium • Lipid derivatives • IP3 • DAG • Many others

  8. Cyclic AMP • Made from ATP • Adenylate cyclase • Membrane effector • Needs a G-protein • Hydrolysis of cAMP to AMP terminates signal

  9. cAMP • Regulates some ion channels as ligand • Regulates a kinase • Phosphorylates many substrates • Substrate determines effect seen • Increase glycogen breakdown • Decrease glycogen synthesis • Increase cardiac beat strength • Etc.

  10. cAMP System • Example of typical second messenger set up • Receptor • G protein • Effector protein • Second messenger • “2nd Messenger binding protein(s)” • Target(s) of ‘SMBPs” • Termination mechanism

  11. cAMP Signaling Path E Gs R cAMP ATP

  12. cAMP Signaling Path E Gs R cAMP + ATP PKA

  13. PDE - cAMP Signaling Path E Gs R cAMP + ATP PKA Substrate-P substrate

  14. Cyclic GMP • Made from GTP • Guanylate cyclase • Membrane or soluble • Acts as receptor • No G-protein involved • Hydrolysis of cGMP to GMP terminates signal

  15. cGMP • Regulates several proteins as ligand • Ion channels • Protein kinase • Important in smooth muscle relaxation • Important in visual system

  16. Calcium as a 2nd Messenger • Low cytoplasmic Ca++ at rest • Channels open with voltage and/or ligands • Channels in PM and in “calciosome”

  17. Calcium as a 2nd Messenger • High cytoplasmic Ca++ when stimulated • Pumps move calcium out of cytoplasm • Pumps in PM and in “calciosome”

  18. Calcium as a 2nd Messenger • Many binding proteins mediate Ca++ action • Activated by calcium • Troponin C • Calmodulin • Calmodulin is multifunctional

  19. Calmodulin Ca++ Ca++ Ca++ Ca++

  20. Calmodulin Ca++ Ca++ Ca++ Ca++

  21. Calmodulin Targets • Adenylate cyclase (some versions) • Phosphodiesterase (some versions) • Myosin light chain kinase • Calmodulin-dependent kinases • Calcineurin (a phosphatase) • And so on…

  22. Inositol tri-phosphate Hydrophilic Agonist for internal calcium channel [Ca++]i rises Multiple effects through Ca++-binding proteins Diacylglycerol Hydrophobic Targets PKC (a kinase) PKC requires Ca++ and DAG Mimicked by phorbol esters (tumorogenic) Phospholipase C as Effector

  23. IP3/DAG Signaling Path PKC E G R Substrate-P substrate IP3 & DAG PI Ca++ calciosome

  24. Why 2nd Messengers? • Complicated pathways • Difficult to understand • Hard to learn • Many parts makes easy to be disrupted • Complexity allows flexibility • More graded cellular responses • Interaction of pathways • Signal amplification

  25. Signals and Effects • Signal is required to produce cellular change • Signal generated by receptor (or effector) • Signal size related to # of active receptors • (dose response!)

  26. Signal Amplification • Example from G protein-coupled receptor • Activated receptor hits several G proteins • Each effector makes/ releases many molecules • 2nd messenger receptor also amplifies, especially if it’s a kinase • Bottom line: one molecule of extracellular ligand generates many modified proteins inside the cell ( a large signal)

  27. Review • Ligand binding alters receptor • Some receptors use signaling molecules • Synthesized from precursors • Released from storage site • Called second messengers • Second messengers activate other proteins • Activation acts as signal, changes things • Second messenger is removed to end signal

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