Receptor G Protein Effector 2nd messenger 2nd Effector

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PROTOTYPICAL GPCR SIGNALING CASCADE
Receptor G Protein Effector 2nd
messenger 2nd Effector Sensory Receptors
Enzymes Enzymes Peptide Receptors
phosphodiesterase cyclic nucleotides
kinases Hormone Receptors adenylate cyclase
lipids
phosphatases Neurotransmitter
phospholipaseA calcium
Receptors phospholipaseC
Ion Channels Ion
Channels
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Receptor G Protein Effector 2nd
messenger 2nd Effector Adrenergic Gs
adenylate cAMP protein kinaseA
receptor(AR) cyclase (AC)
(PKA) metabotropic Gq
phospho- IP3 and DAG Ca release Glutamate
lipaseC Receptor (mGluR)
(PLC)
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Families of Receptors

• IONOTROPIC Heteromultimer
• (GABAa, nAChR)
• 2. METABOTROPIC Monomer? Dimer? (mGluR,
  peptides)
• RECEPTOR Dimer
• TYROSINE KINASE
• (growth factors)

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Different flavors of RTKs---extracellular domains
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Different flavors of RTKs---intracellular domains
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How a receptor tyrosine kinase works
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Why study RTKs?
One reason RTKs are important in cancer 1)
Expose mice to radiation 2) neural ectoderm
forms tumors 3) DNA from tumor can
transform tissue culture cells 4) Isolate the
gene HER2 RTK (human EGF receptor 2)
normal
cancerous
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The Her-2 mutation is found in 20-25 of all
breast cancers The mutation is a single amino
acid substitution in TM domain The Her-2
mutation is always active! RTK is always on!
Tumors in Her-2 mutant mice
Does it cause breast cancer? ---Mice with
activated Her-2 develop mammary
tumors ---Never males ---Never non-transgenic
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MAPK mitogen-activated protein kinase RTK
receptor tyrosine kinase
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Signal transduction for RTKs
Scaffold proteins tether many molecules together
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Different scaffold proteins mediate different
responses
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Different scaffold proteins mediate different
responses
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Signaling cascades change the activity of many
proteins within the cell
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• Signaling through channels versus GPCRs, RTKs
• channel cascade
• Kinetics ms seconds
• Spatial spread local global
• Gain low high
• Regulation channel all steps

Channels are fast ON-OFF switches GPCR/RTK
cascades are slow relays with diverse outputs
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Enzymatic cascades provide amplification of
original signal
1R 10Gs 10ACs 1000-10,000 cAMP
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How do signaling cascades affect neural activity?

• Regulation of ion channel activity
• through 2nd messengers
• through G proteins
• through transcriptional activation

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