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Cellular Signaling
Montarop YamabhaiSuranaree University of Technology
Out line
I. Principle of Cellular SignalingII. Nuclear ReceptorIII. G Protein-Couple Receptors (GPCR) and
Second MessengersIV. Receptor Tyrosine KinasesV. Other Signaling PathwayVI. Interaction and Regulation of Signaling
PathwayVII. Target intervention in Signal
Transduction
I. Principle of cellular signaling
• Extracellular signal molecules bind to specific receptors
• There are two types of receptors• There are 5 types of intercellular signaling• Identification and purification of cell surface
receptor• Responses from cellular signaling• There are three majors classes of cell-surface
receptor• Multiple steps of cell signaling • Different types of intracellular signaling proteins• Methods that are used to study protein-protein
interaction
There are two types of receptors:
Ligands that bind to intracellular receptors
Ligands that bind to cell surface receptors
• Water soluble hormone and neuro transmitters– Peptide hormones– Small charged hormones and neurotransmitters
• Prostaglandin and other eicosanoid hormones
Small molecules that function as neurotransmitters
Eicosanoid hormones
5 Types of Intercellular Signaling
1. Endocrine signaling
2. Paracrine signaling
3. Synaptic signaling
4. Autocrine signaling
5. Signaling by plasma membrane-attached proteins
Identification of cell surface receptor
Purification of cell surface receptor
Basic Components and Responses of Cellular Signaling
Activation/repression ofDNA/RNA synthesis
Chage in ion permeability
3 Types of Cell-Surface-Receptors
1. Ion-channel-linked receptors
2. G-protein-coupled receptors
3. Enzyme-linked receptors
Multi steps of signaling pathway
• Recognition of stimulus by cell surface receptor
• Transfer of signal across plasma membrane
• Transmission of the signal to specific targets inside the cells
• Cessation of the responses
Types of Signaling Protiens
1. Proteins Kinases / Phosphatases. These are proteins that involve in phosphorylation reactions
2. Proteins or GTP-binding proteins3. Adaptor and scaffold proteins
Protein Kinases & Phosphatases
Final Target
G-Protein
Accessory proteins 1. GTPase-activating proteins (GAPs)2. Guanine nucleotide-exchange factors (GEFs)3. Guanine nucleotide-dissociation inhibitors (GDIs)
Adaptor Protein
Scaffold Proteins
Detection of Protein-Protein Interaction by Yeast two-hybrid system
Detection of Protein-Protein Interaction by Phage Display Technology
Nuclear Receptor(Ligand-activated Gene Regulartory Protein)
Responses induced by the activation of a nuclear hormone
G Protein-Couple Receptors (GPCR) and Second
Messengers
1. Structure and Function of G protein-couple receptor
2. Second messengers3. The specificity of G protein-coupled
responses4. The role of G-protein-coupled receptors
in sensory perception
G protien-coupled receptor
Seven membrane spanning helices
G protein binds to guanine nucleotides, eitherGDP or GTP. It consists of three different polypeptide subunits, called , , and .
Mechanism of activation of GPCR
1. activation of the G protein by the receptor- Activation of adenylate cyclase to generate cAMP- Activation of phospholipase C to generate IP3
and DAG
2. relay of the signal from G protein to effector3. ending of the response
I. Activation of the G protein by the receptor
II. Relay of the signal from G protein to effector
III. Ending of the response
The synthesis and degradation of cAMP
-adrenergic receptors mediate the induction of epinephrine-initiated cAMP
synthesis
Agonist and of the -adrenergic receptors
-Epinephrine-isoproterenol
Antagonist of the -adrenergic receptors
-Alprenolol-Propranolol-Practolol
Hormone-induced activation and inhibition of adenylate
cyclase
Activation of cAMP-dependent protein kinase (PKA) by cAMP
Table 1
A sample of known PKA substrates
• Muscle glycogen synthase (Ia)• Phosphorylase kinase • Protein phosphatase-1• Pyruvate kinase• CREB• Liver tyrosine hydroxylase• Acetylcholine receptor • Protein phosphatase inhibitor -1• S6 ribosomal proteins• Rabbit heart troponin• Hormone sensitive lipase• Phosphofructokinase• Myosin light-chain kinase• Fructose biphosphatase• Phosphorylase kinase • Musle glycogen synthase• Acetyl CoA carboxylase
A variety of responses from cAMP signaling
• Plasma membrane: transport• Microtubule: assembly and disassembly• Endoplasmic recticulum: protein synthesis• Nucleus: DNA synthesis, gene expression• Mitochondria and cytosol: glycogen break
down (phosphorylase) in liver, glycogen synthase, triglyceride lipase (fatty acid formation in fat cells
QuickTime™ and aAnimation decompressorare needed to see this picture.
Activation of gene transcription by a rise in cAMP
Regulation of glycogen breakdown and synthesis by cAMP in liver and muscle cells
The role of cAMP in glucose metabolism in liver cells
Amplification of the signal via cAMP signaling pathway
The generation of phosphatidyl inositol-derived second messengers
Protein Kinase C (PKC) is activated by inositol phospholipid pathway
QuickTime™ and aAnimation decompressorare needed to see this picture.
Elevation of Ca2+ via the inositol lipid signaling pathway
Table 20-4. Cellular Responses to Hormone-Induced Rise in Inositol 1,4,5-Trisphosphate (IP3) and Subsequent Rise in Cytosolic Ca2+ in Various Tissues
Tissue Hormone Inducinga Rise in IP3
Cellular Response
Pancreas (acinar cells)
Acetylcholine Secretion of digestive enzymes, such as amylase and trypsinogen
Parotid (salivary gland)
Acetylcholine Secretion of amylase
Pancreas ( cells of islets)
Acetylcholine Secretion of insulin
Vascular or stomach smooth muscle
Acetylcholine Contraction
Liver Vasopressin Conversion of glycogen to glucose
Blood platelets Thrombin Aggregation, shape change, secretion of hormones
Mast cells Antigen Histamine secretion
Fibroblasts Peptide growth factors, such as bombesin and PDGF
DNA synthesis, cell division
Sea urchin eggs Spermatozoa Rise of fertilization membrane
SOURCE: M. J. Berridge, 1987, Ann. Rev. Biochem. 56:159; M. J. Berridge and R. F. Irvine, 1984, Nature
Ca2+ Calmodulin mediates many cellular responses
The specificity of G protein-coupled responses
• GPCRs link to different G protein
• G protein regulate different effector proteins
Table 20-5. Properties of Mammalian G Proteins Linked to GPCRs
G Subclass Effect Associated Effector Protein 2nd Messenger
Gs Adenylyl cyclase cAMP
Ca2+ channel Ca2+
Na+ channel Change in membrane potential
Gi Adenylyl cyclase cAMP
K+ channel Change in membrane potential Ca2+ channel Ca2+
Gq Phospholipase C IP3, DAG
Go Phospholipase C IP3, DAG
Ca2+ channel Ca2+
Gt cGMP phosphodiesterasec GMP
G Phospholipase C IP3, DAG
Adenylyl cyclase cAMP
The specificity of G protein-coupled responses
G protein in receptor sensory
Response of a rod photoreceptor cell to light
Receptor Tyrosine Kinases (RTKs)
Activation of RTKs
Ras function downstream of RTKs
Activation of Ras by RTKs
Ras activate MAP Kinase Cascade
Insulin Signaling Pathway
IV Other Signaling Pathways
• Other enzyme-linked signaling pathway– Jak-STAT signaling pathway– TGF-b signaling pathway
• Signaling pathways that depend on regulated proteolysis– Wnt signaling pathway– TNF-a signaling pathway
• Nitric oxide signaling pathway• Apoptotic pathway• Signaling from contacts between cell
surface and the substratum
Activation of Jak-STAT pathway by Cytokine Receptors
TGF- Pathway
Wnt Signaling Pathway
TNF- signaling Pathway
Nitric Oxide (NO) Signaling
Apoptotic Pathway
Signaling from contacts between cell surface and the substratum