Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CytoplasmExternal environment Membrane receptor Intracellular receptor Plasma membrane Signal transduction pathway Signal transduction pathway Cellular response Cellular response Hydrophobic ligand Hydrophilic ligand 1

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a.b.c.d. Synaptic SignalingEndocrine SignalingParacrine Signaling Nerve cell Neurotransmitter Synaptic gap Target cell Blood vessel Distant target cells Secretory cell Direct Contact Adjacent plasma membrane Plasma membrane Adjacent target cells Hormone secretion into blood by endocrine gland Adjacent plasma membrane Plasma membrane 2

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Kinase Phosphatase Kinase Phosphatase O P O–O– OO–O– O P O–O– OO–O– OH Tyr ADP PiPi ATP Ser or Thr Ser or Thr Tyr PiPi 3

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a. c. b. Ions Ligand (signal) Inactive Active        GDP GTP Ions G protein EnzymeIon channel GPCR G protein activates either enzyme or ion channel Ligand (signal) Cellular response Ligand (signal)        4

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormone Inhibitor 1. Hormones cross plasma membrane and bind to cytoplasmic receptors. 2. Hormone binding alters receptor conformation so it no longer binds inhibitor. 5. Cellular response is a change in gene expression. 3. Hormone–receptor complex translocates to nucleus. 4. Hormone–receptor complex binds to DNA. This usually turns on transcription, but can also turn it off. Signal molecule- binding domain DNA-binding site exposed DNA-binding site blocked Transcription-activating domain Gene transcription 5

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligands Phosphorylated protein Intracellular kinase domain Extracellular ligand-binding domain P P P P P P P P P P P P P P P P P P Phosphate groups Transmembrane RTK proteins 1. Ligand binds to the receptor. 2. Two receptors associate (dimerize) and phosphorylate each other (autophosphorylation). 3. Response proteins bind to phospho- tyrosine on receptor. Receptor can phosphorylate other response proteins. Dimerization and autophosphorylation Cellular response 6

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Signal amplification Signal Response Receptor Signal Receptor Activator Cellular responses MKK MK Active Inactive Active MKKK MKK MK MKKK Response proteins a. b. Ras P P P P P P MAP kinase cascade First kinase Second kinase MAP kinase Response proteins Cellular response Response proteins Response proteins MKKK MKK MK MKKK MKK MK MKKK MKK MK MKKK MKK MK Response proteins 7

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. P –O–O –O–O O O P –O–O –O–O O O POCH 2 O O a. b. Extracellular space Cytoplasm Phospholipase C PIP 2 O C O C O CC O C O P O O –O–O P O OO–O– O–O– P O–O– OO–O– O OH DAG + IP 3 O C O C O CC O C OH P O O O O–O– P O OO–O– O–O– P O–O– OO–O– O P –O–O OO O O CH 2 DAG IP 3 P O–O– –O–OO O P O–O– O–O– O PP i cAMP Adenylyl cyclase NH 2 N N ATPcAMP + PP i Plasma membrane Cleaved by phospholipase C 8

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligand GPCR GDPGTP ATP Activates PKA Cellular response Response protein Response protein Adenylyl cyclase Cytoplasm Nucleus cAMP         9

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ca 2+ ER Cytoplasm Phospholipase C GPCR DAG PIP IP 3      Cellular response Ca 2+ binding protein      Ligand GDP GTP 10

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ca 2+ Calmodulin a.b. Active protein Inactive protein Ca 2+ 11

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. P Cytoplasm Epinephrine Glucagon PPP PPPP Glycogen CH 2 GD P P GPCR PKA cAMP Glucose-6-phosphate Adenylyl cyclase Adenylyl cyclase Phosphorylase kinase Glycogen phosphorylase GTP P ATP 12