Second Messengers and Signal Transduction

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2. Overview. Signal transduction- a conceptSecond messengersCharacteristicsExamplesBenefits . 3. Signal Transduction. Intracellular communicationDetection of extracellular eventGeneration of internal changeBottom line- presence of external ligand causes a change inside cell. 4. Signaling Examples.
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. 2 Overview Signal transduction- a concept Second messengers Characteristics Examples Benefits

3. 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. 4 Signaling Examples Ligands Estrogen Acetylcholine Insulin Epinephrine Receptors Transcription factor Sodium channel Receptor kinase G protein-coupled receptor

5. 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) Second messengers are not exclusively found in the path of G protein-coupled receptors- other receptor signal paths can also use second messengersSecond messengers are not exclusively found in the path of G protein-coupled receptors- other receptor signal paths can also use second messengers

6. 6 Second Messengers General characteristics Low amounts in resting state Regulated synthesis Regulated destruction Act through other proteins Acting through other proteins can be a make-or-break part of the definition. There are many molecules whose synthesis and destruction are regulated that DO NOT act as second messengers because their presence does not prompt proteins to change their behavior, i.e. because they do not act as a signal.Acting through other proteins can be a make-or-break part of the definition. There are many molecules whose synthesis and destruction are regulated that DO NOT act as second messengers because their presence does not prompt proteins to change their behavior, i.e. because they do not act as a signal.

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

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

9. 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. 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 Remember: receptors other than G protein-coupled receptors may use second messengerRemember: receptors other than G protein-coupled receptors may use second messenger

11. 11 cAMP Signaling Path

12. 12 cAMP Signaling Path

13. 13 cAMP Signaling Path

14. 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. 15 cGMP Regulates several proteins as ligand Ion channels Protein kinase Important in smooth muscle relaxation Important in visual system

16. 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. 17 Calcium as a 2nd Messenger High cytoplasmic Ca++ when stimulated Pumps move calcium out of cytoplasm Pumps in PM and in ?calciosome?

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

19. 19 Calmodulin

20. 20 Calmodulin This change in shape allows calcium-bound calmodulin to bind (and regulate) other proteinsThis change in shape allows calcium-bound calmodulin to bind (and regulate) other proteins

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

22. 22 Phospholipase C as Effector 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) This enzyme (PLC) can be activated in a number of ways, one of which is by a G-protein. When on, PLC synthesizes the two second messengers described above.This enzyme (PLC) can be activated in a number of ways, one of which is by a G-protein. When on, PLC synthesizes the two second messengers described above.

23. 23 IP3/DAG Signaling Path

24. 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. 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. 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) With cyclic AMP as a specific example: one epinephrine molecule binds its receptor; multiple G proteins are activated by the activated receptor (more than one per epinephrine molecule = amplification); each G protein activates one adenylate cyclase enzyme (one-to-one = no amplification); each adenylate cyclase makes many molecules cyclic AMP (amplification); cyclic AMP activates a kinase which phosphorylates many substrates (more amplification) With cyclic AMP as a specific example: one epinephrine molecule binds its receptor; multiple G proteins are activated by the activated receptor (more than one per epinephrine molecule = amplification); each G protein activates one adenylate cyclase enzyme (one-to-one = no amplification); each adenylate cyclase makes many molecules cyclic AMP (amplification); cyclic AMP activates a kinase which phosphorylates many substrates (more amplification)

27. 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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