1. Receptor G Protein Effector 2 nd messenger 2 nd 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 PROTOTYPICAL GPCR SIGNALING CASCADE LAST TIME 1

2. 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) 2

3. 1.IONOTROPICHeteromultimer (GABAa, nAChR) 2. METABOTROPICMonomer? Dimer? (mGluR, peptides) 3.RECEPTORDimer TYROSINE KINASE (growth factors) Families of Receptors 7

4. 9 Different flavors of RTKs---extracellular domains

5. 10 Different flavors of RTKs---intracellular domains

6. How a receptor tyrosine kinase works 11

7. 12

8. 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) Why study RTKs? normal cancerous13

9. Does it cause breast cancer? ---Mice with activated Her-2 develop mammary tumors ---Never males ---Never non-transgenic 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 14

10. 8 MAPK= mitogen-activated protein kinase RTK= receptor tyrosine kinase

11. 16

12. 15 Scaffold proteins tether many molecules together Signal transduction for RTKs

13. Different scaffold proteins mediate different responses 17

14. Different scaffold proteins mediate different responses 18

15. Signaling cascades change the activity of many proteins within the cell 19

16. Signaling through channels versus GPCRs, RTKs channel cascade 1.Kineticsmsseconds 2.Spatial spread localglobal 3.Gain lowhigh 4.Regulation channelall steps Channels are fast ON-OFF switches GPCR/RTK cascades are slow relays with diverse outputs 20

17. Enzymatic cascades provide amplification of original signal 21 1R 10Gs 10ACs 1000-10,000 cAMP

18. How do signaling cascades affect neural activity? Regulation of ion channel activity –through 2 nd messengers –through G proteins –through transcriptional activation 22