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External environment Cytoplasm

Signal Cellular transduction response pathway

Membrane receptor

Signal Cellular transduction Hydrophilic response pathway ligand

Intracellular receptor

Hydrophobic ligand Plasma membrane

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Direct Contact Paracrine Signaling Endocrine Signaling Synaptic Signaling Secretory cell Hormone secretion into 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.

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ATP ADP O Ser Ser Kinase or OH or O P O– Thr Thr

Phosphatase O–

Pi

ATP ADP O Kinase Tyr OH Tyr O P O–

Phosphatase O–

Pi

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Ions Ligand (signal)

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 Hormone conformation so it no Inhibitor 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.

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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.

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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 MKK P Response proteins kinase MKKMKK Active Inactive P P MAP Cellular responses MK P kinase MK Active Inactive b.

Response Response proteins proteins

Response Cellular 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 – N N O P O P O P O CH CH2 2 O O Adenylyl cyclase PP i –O –O –O O O O

O P O –O P O P O–

–O O– O– a. Extracellular space

Plasma membrane

O C C O O C C O O O O O DAG – C C C O Cytoplasm C C C – O O P O OH O–

–O O Cleaved by O P O– P O O phospholipase C O O– P O O OH Phospholipase C OH OH O O OH OH OH O P O– 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

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Ligand

GPCR Phospholipase C

β γ β γ α PIP GDP GTP DAG

IP 3 Cytoplasm

Ca2+ binding protein ER

Ca2+ Cellular response

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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