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LAST TIME PROTOTYPICAL GPCR SIGNALING CASCADE Receptor G Protein Sensory Receptors Peptide Receptors Hormone Receptors Neurotransmitter Receptors Effector 2nd messenger Enzymes phosphodiesterase adenylate cyclase phospholipaseA phospholipaseC 2nd Effector Enzymes cyclic nucleotides kinases lipids phosphatases calcium Ion Channels Ion Channels 1 Receptor G Protein Adrenergic receptor(AR) Gs metabotropic Gq Glutamate Receptor (mGluR) Effector 2nd messenger 2nd Effector adenylate cyclase (AC) phospholipaseC (PLC) cAMP protein kinaseA (PKA) IP3 and DAG Ca release 2 Families of Receptors 1. IONOTROPIC (GABAa, nAChR) Heteromultimer 2. METABOTROPIC (mGluR, peptides) Monomer? Dimer? 3. RECEPTOR TYROSINE KINASE (growth factors) Dimer 7 Different flavors of RTKs---extracellular domains 9 Different flavors of RTKs---intracellular domains 10 How a receptor tyrosine kinase works 11 12 Why study RTKs? One reason: RTKs are important in cancer normal 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) 13 cancerous 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 14 MAPK= mitogen-activated protein kinase RTK= receptor tyrosine kinase 8 16 Signal transduction for RTKs Scaffold proteins tether many molecules together 15 Different scaffold proteins mediate different responses 17 Different scaffold proteins mediate different responses 18 Signaling cascades change the activity of many proteins within the cell 19 Signaling through channels versus GPCRs, RTKs channel cascade 1. Kinetics ms seconds 2. Spatial spread local global 3. Gain low high 4. Regulation channel all steps Channels are fast ON-OFF switches GPCR/RTK cascades are slow relays with diverse outputs 20 Enzymatic cascades provide amplification of original signal 1R 10Gs 10ACs 1000-10,000 cAMP 21 How do signaling cascades affect neural activity? Regulation of ion channel activity – through 2nd messengers – through G proteins – through transcriptional activation 22
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