Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. External environment Cytoplasm Signal Cellular transduction response pathway Membrane receptor Signal Cellular transduction Hydrophilic response pathway ligand Intracellular receptor Hydrophobic ligand Plasma membrane 1 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Direct Contact Paracrine Signaling Endocrine Signaling Synaptic Signaling Hormone secretion into Secretory cell Nerve cell blood by endocrine gland Neurotransmitter Adjacent plasma membrane Blood vessel Synaptic gap Plasma Adjacent membrane target cells Distant target cells Target cell a. b. c. d. 2 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ATP ADP O Ser Ser Kinase or OH or O P O– Thr Thr Phosphatase O– Pi ATP ADP O Kinase Tyr Tyr – OH O P O – Phosphatase O Pi 3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligand (signal) Ions Ligand (signal) Inactive Active Cellular Ions response a. b. Ligand (signal) Ions GPCR γ γ β β G protein α Ion channel Enzyme α α GDP G protein activates GTP GTP either enzyme or ion channel c. 4 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 2. Hormone binding alters receptor 5. Cellular Inhibitor Hormone conformation so it no response is longer binds inhibitor. a change in Signal molecule- gene binding domain expression. DNA-binding site exposed 1. Hormones cross plasma membrane and bind to cytoplasmic Inhibitor receptors. DNA-binding 3. Hormone–receptor site blocked complex translocates Gene Transcription-activating domain to nucleus. transcription 4. Hormone–receptor complex binds to DNA. This usually turns on transcription, but can also turn it off. 5 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligands P P P P Phosphate P P P groups P P P P P P P P P P P Dimerization and Cellular autophosphorylation response Transmembrane RTK proteins Phosphorylated protein Intracellular kinase domain Extracellular ligand-binding domain 2. Two receptors associate (dimerize) 3. Response proteins bind to phospho- 1. Ligand binds to the receptor. and phosphorylate each other tyrosine on receptor. Receptor can (autophosphorylation). phosphorylate other response proteins. 6 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. MAP kinase cascade Signal amplification Signal Signal Receptor Receptor Activator MKKKMKKK MKKKMKKK Activator Ras MKKMKK MKKMKK MKK First MKKKMKKK kinase MKKKMKKK Active Inactive MK MK MK MK P P Second Response proteins MKK P kinase MKKMKK Active Inactive P P MAP Cellular responses kinase MK P MK Active Inactive b. Response Response proteins proteins Cellular Response response a. 7 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ATP cAMP + PPi NH NH2 2 cAMP O O O –O N CH N P O P O P O CH2 2 O O Adenylyl cyclase PP i – – – O O O O O O –O P O P O– O P O – – – O O O a. Extracellular space Plasma membrane O C C O O C C O O O O O DAG O– Cytoplasm C C C C C C O P O– – O OH O –O P O O Cleaved by O P O– O phospholipase C O – O O P O OH OH OH Phospholipase C O O OH OH OH – O O P O – O– IP O P O 3 O– PIP DAG + IP 2 3 b. 8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligand Adenylyl cyclase GPCR β γ γ β γ γ α GDP GTP cAMP ATP Cytoplasm Activates PKA Response protein Cellular Nucleus response 9 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ligand GPCR Phospholipase C β γ β γ α PIP GDP GTP DAG IP 3 Cytoplasm Ca2+ binding protein ER Ca2+ Cellular response 10 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ca2+ Ca2+ Ca2+ Inactive protein Calmodulin Calmodulin Ca2+ Active Ca2+ protein a. b. 11 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Epinephrine Adenylyl GPCR cyclase Adenylyl cyclase Glucagon GTP GTP GD P ATP ATP cAM P PK A GD P Cytoplasm P P P P Phosphorylase kinase P P P P Glycogen phosphorylase P CH 2 Glycogen Glucose-6-phosphate 12 .