second messengers and signal transduction tim bloom, ph.d. 104a hall of science 893-1712
TRANSCRIPT
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Second Messengers and Signal Transduction
Tim Bloom, Ph.D.
104A Hall of Science
893-1712
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Overview
• Signal transduction- a concept
• Second messengers– Characteristics– Examples– Benefits
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Signal Transduction
• Intracellular communication– Detection of extracellular event– Generation of internal change
• Bottom line- presence of external ligand causes a change inside cell
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Signaling Examples
• Ligands – Estrogen
– Acetylcholine
– Insulin
– Epinephrine
• Receptors – Transcription factor
– Sodium channel
– Receptor kinase
– G protein-coupled receptor
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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)
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Second Messengers
• General characteristics– Low amounts in resting state– Regulated synthesis– Regulated destruction– Act through other proteins
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Second Messengers
• Cyclic nucleotides– cAMP– cGMP
• Calcium
• Lipid derivatives– IP3
– DAG– Many others
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Cyclic AMP
• Made from ATP• Adenylate cyclase
– Membrane effector
– Needs a G-protein
• Hydrolysis of cAMP to AMP terminates signal
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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.
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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
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cAMP Signaling Path
RGs
E
ATP
cAMP
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cAMP Signaling Path
RGs
E
ATP
cAMP
PKA
+
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cAMP Signaling Path
RGs
E
ATP
cAMP
PKA
+
substrate Substrate-P
PDE-
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Cyclic GMP
• Made from GTP• Guanylate cyclase
– Membrane or soluble
– Acts as receptor
– No G-protein involved
• Hydrolysis of cGMP to GMP terminates signal
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cGMP
• Regulates several proteins as ligand– Ion channels– Protein kinase
• Important in smooth muscle relaxation
• Important in visual system
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Calcium as a 2nd Messenger
• Low cytoplasmic Ca++ at rest
• Channels open with voltage and/or ligands
• Channels in PM and in “calciosome”
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Calcium as a 2nd Messenger
• High cytoplasmic Ca+
+ when stimulated
• Pumps move calcium out of cytoplasm
• Pumps in PM and in “calciosome”
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Calcium as a 2nd Messenger
• Many binding proteins mediate Ca++ action
• Activated by calcium– Troponin C– Calmodulin
• Calmodulin is multifunctional
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Calmodulin
Ca++ Ca++
Ca++ Ca++
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Calmodulin
Ca++
Ca++ Ca++
Ca++
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Calmodulin Targets
• Adenylate cyclase (some versions)
• Phosphodiesterase (some versions)
• Myosin light chain kinase
• Calmodulin-dependent kinases
• Calcineurin (a phosphatase)
• And so on…
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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)
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IP3/DAG Signaling Path
RG
E
PI
IP3 & DAG
PKC
substrateSubstrate-P
calciosome
Ca++
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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
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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!)
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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)
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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