Chapter 8 Signal Transduction Events

a general process of signal transduction pathway

Singnaling Molecules

Receptors for Water-solulble Signaling Molecules Gated channels Gated channels Catalytic receptors Catalytic receptors Receptors coupled to G protein Receptors coupled to G protein

Receptors for Lipid-soluble Singaling Molecules Steroid Hormones HAT : histone acetyltransferase

(Histone transacetylase) (Histone deacetylase) Thyroid Hormones

Catalytic Receptors/Tyrosine Kinases Catalytic Receptors/Tyrosine Kinases

Organization of Receptor Protein- Tyrosine Kinases

Structure of Protein Kinases cAMP-dependent protein kinases Ca 2+ -calmodulin-dependent protein kinases PDGF receptor kinases

FGF Signal Transduction Pathway PKD : protein kinase D, PKC : protein kinase C, PDK : phosphoinositide-dependent kinase, DAG : diacylglycerol

Activation of Ras following ligand binding to receptor tyrosine kinase (1) (growth factor receptor-bound protein 2) (Srk homology 2,3) (Epithermal growth factor) (Growth factor receptor-bound protein 2) (Son of sevenless)

A signal transduction from Ras to MAP kinase (2) mitogen-activated or extracellular-signal-regulated protein kinase (MEK) mitogen-activated protein kinase (MAPK)

Induction of gene transcription by activated MAP kinase (3) Transcription factor (TCF) Serum response factor (SRF) Serum responsive element (SRE)

ErbB-induced Signaling Pathway

JAK-STAT signaling pathway of cytokine receptors

Pathways of MAP Kinase Activation in Mammalian Cells

TGF-  and TGF  -like Ligands/Their Type I and II Receptors

TGF-  Receptor-mediated Signaling 6

Two signalling pathways of the TGF-  superfamil y

Nodal-mediated Signaling for Determination of Left-right Asymmetry

Wnt Signaling Pathway

Hedgehog Cleavage and Singling Pathway

Notch-mediated Signaling Pathway

Signaling Network Model for Heart Valve Development

Steroid Hormone-mediated Signaling Pathway

(Histone transacetylase) (Histone deacetylase) Thyroid Hormone-mediated Signaling Pathway

G Protein-Linked Receptors G Protein-Linked Receptors

Structure of a G Protein-Coupled Receptor

Operational Model of G Protein-coupled Receptors

Synthesis and Degradation of cAMP

Regulation of Protein Kinase A

Regulation of Glycogen Metabolism by cAMP

Amplification of an External Signal Downstream from a Cell-surface Receptor

Activation and Inhibition of Adenylate Cyclase (Adnocorticotropic hormone)

Operational Model of Muscarinic Acetylcholine Receptor

Transducin (G t )-mediated signal transduction PDE: cGMP Phosphodiesterase

Cyclic AMP-Inducible Gene Expression (cyclic AMP-response element binding protein)

Renin-antiotensin-aldosterone System

Ion Channel-linked Receptors Ion Channel-linked Receptors

Structure of Representative Neurotransmitters (Na + influx) (Cl - influx)

Architecture of Ligand-gated Receptors

The Nicotinic Acetylcholine Receptor *Muscarinic acetylcholine receptor

The GABA Receptor *GABA B receptors are coupled to an intracellular G-protein and act by increasing conductance of an associated K + channel. ReceptorGABA A GABA B GABA C Effector Chloride channel G i/o Chloride channel Agonists Muscimol, THIP Baclophen- Antgonist s BicucullinSaclofen-

Psychoactive drugs and GABA receptors inhibitory Cl - channels a GABA A receptor two GABA-binding sites (αβ) a benzodiazepine- binding site(αγ) barbiturates-binding sites(αβ)

The Glutamate Receptor excitatory cation channels: Na +, K +, and Ca 2+ kainate receptor, quisqhalate A receptor AMPA (  -amino-3-hydroxyl-5-methyl-4- isoxazole-propionate) receptor NMDA (N-methyl-D-aspartate) receptor permeable to responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie learning and memory. *quisqualate B receptor: activation of a PI-linked second messenger pathway

The signaling events on long-term potentiation

Calcium as a Second Messenger Calcium as a Second Messenger

Ca 2+ Influx and Efflux Ca 2+ Influx Ca 2+ Influx By gated Ca 2+ channels in plasma membranes By gated Ca 2+ channels in plasma membranes By Ca 2+ channels in intracelluar organelles (ER, SR) By Ca 2+ channels in intracelluar organelles (ER, SR) Ca 2+ Efflux Ca 2+ Efflux By Ca 2+ -ATPase in plasma membranes By Ca 2+ -ATPase in plasma membranes By Ca 2+ -ATPase in intracelluar organelles (ER, SR) By Ca 2+ -ATPase in intracelluar organelles (ER, SR) By accessory Ca 2+ pumps (Ca 2+ /Na + antiporter) By accessory Ca 2+ pumps (Ca 2+ /Na + antiporter)

IP3- and DAG-mediated Signaling Activation of Gq Activation of Gq → interaction of G qα -subunit with phospholipase C-β (activation) → hydrolysis of phosphoinositol biphosphate (PIP 2 ) to inositol triphosphate (IP 3 ) and Diacylglycerol (DAG) → IP 3 binding to IP 3 receptors (a gated Ca 2+ channel) of ER → intracellular Ca 2+ release →→ activation or inhibition of target proteins Recovery of the intracellular Ca 2+ level Recovery of the intracellular Ca 2+ level Ca 2+ ATPases: pumping out of cytoplasm Ca 2+ ATPases: pumping out of cytoplasm dephosphorylation of IP 3 by a phosphatase dephosphorylation of IP 3 by a phosphatase

Activity of PI 3-Kinase

Hydrolysis of PIP 2

Activation of Phospholipase C-β by G Protein (G q )-coupled receptors

Ca 2+ Mobilization by IP 3

Activation of Phospholipase C-γ by Protein-Tyrosine Kinases

Function of Calmodulin Adenylate cyclase isozymes, cAMP phosphodiesterases,

Ca 2+ Influx and Neurotransmitter Release

Ca 2+ influx and exocytosis of synaptic vesicles

Rizo and Sudhof 2002, Nature Rev. Neurosci.

Axo-axonic synapse

Signaling Events on Long-term Potentiation

Regulation of Intracellular Ca 2+ in Electrically Excitable Cells

Activation of the Akt protein Kinase - The serine/threonine protein kinase Akt/PKB is the cellular homologue of the viral oncogene v-Akt and is activated by various growth and survival factors (Akt1, Akt2, and Akt3). - PI3K generates phosphorylated phosphatidylinositides (PIP2, PIP3) that bind to Akt. - PIP2 and PIP3 also activate PDK which phosphorylates Akt. - Activated Akt promotes cell survival through two distinct pathways: 1) Akt inhibits apoptosis by phosphorylating the Bad component of the Bad/Bcl- XL complex. 2) Akt activates IKK-a that ultimately leads to NF-kb activation and cell survival.

Integrin Signaling

Apoptosis

Regulators and Effectors of Apoptosis

Cell Death Receptors

The PI 3-Kinase Pathway and Cell Survival