cell signaling and regulation of metabolism by dr. amr s. moustafa, md, phd clinical chemistry unit...
TRANSCRIPT
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Cell Signaling and Regulation of Metabolism
By
Dr. Amr S. Moustafa, MD, PhDClinical Chemistry Unit
Department of PathologyCollege of Medicine, King Saud University
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Objectives Different steps in signaling pathways
The second messenger systems
Function of signaling pathways for
Signal transmission
Amplification
The role signaling pathways in regulation and integration of metabolism
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No cell lives in isolation
• Cells communicate with each other• Cells send and receive information (signals)• Information is relayed within cell to
produce a response
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Signaling Process
• Recognition of signal– Receptors
• Transduction– Change of external signal into intracellular
message with amplification and formation of second messenger
• Effect–Modification of cell metabolism and function
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General Signaling Pathway
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Signaling Cascades
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Recognition
• Performed by receptors
• Ligand will produce response only in cells that have receptors for this particular ligand
• Each cell has a specific set of receptors
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Different Responses to the Same Signaling Molecule(A) Different Cells
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Different Responses to the Same Signaling Molecule(B) One Cell but, Different Pathways
HypoglycemiaGlucagon secretion
Hepatocyte: Glucagon/receptor bindingSecond messenger: cAMP
Response: Enzyme phosphorylation
Glycogen synthase(Inactive form)
Inhibition of glycogenesis
Glycogen phosphorylase(Active form)
Stimulation of glycogenolysis
P P
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GTP-Dependant Regulatory Proteins(G-Proteins)
G-Proteins: Trimeric membrane proteins (αβγ)G-stimulatory (Gs) and G-inhibitory (Gi)Binds to GTP/GDP
Inactive form Trimeric –bound GDP
(αβγ/GDP)
Active form α-bound GTP
(α/GTP)
Forms of G-Proteins
The α-subunit has intrinsic GTPase activity, resulting in hydrolysis of GTP into GDP and inactivation of G-proteins
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Signaling Pathways for Regulation of Metabolism
Two important second messenger systems:
Adenylyl cyclase system
Calcium/phosphatidylinositol system
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Adenylyl cyclase
Adenylyl cyclase: Membrane-bound enzymeConverts ATP to cAMP
Activation/Inhibition:Signal: Hormones or neurotransmitters
(e.g., Glucagon and epinephrine) or toxins (e.g., Cholera and pertussis toxins)
Receptor: G-protein coupled receptor
Response: Activation/inhibition of protein kinase A(cAMP-dependent protein kinase)
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Signal Transduction:Adenylyl Cyclase System
Ligand/Receptor Binding
Activation of Gs-protein
Resting state: No Signal
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Signal Transduction:Adenylyl Cyclase System
Activation of adenylyl cyclase
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1 AMP
1Phosphodiesterase
Adenylyl Cyclase System:cAMP-Dependent Protein Kinase
(Protein Kinase A)
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1 AMP
1Phosphodiesterase
Termination of Signal (A)
Protein phosphatase
Phosphodiesterase
cAMP
Inactive protein kinase
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Termination of Signal (B)
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Termination of Signal (C)
Х
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G-Protein Coupled Membrane Receptor
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Regulation of Glycogen Metabolism by Glucagon:Effects on Glycogen Synthase and Phosphorylase
HypoglycemiaGlucagon secretion
Hepatocyte: Glucagon/receptor bindingSecond messenger: cAMP
Response: Enzyme phosphorylation
Glycogen synthase(Inactive form)
Inhibition of glycogenesis
Glycogen phosphorylase(Active form)
Stimulation of glycogenolysis
P P
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Pyruvate Kinase Regulation:Covalent Modification
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Calcium/Phosphatidylinositol System
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Calcium/Phosphatidylinositol System
Phospholipase C
Diacylglycerol (DAG)
Inositol Trisphosphate(IP3)
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Intracellular Signaling by Inositol trisphosphate
e.g., Antidiuretic hormone (ADH)
Acetylcholine
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Signal Amplification
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Cell signaling allows
• Signal transmission and amplification
• Regulation of metabolism
• Intercellular communications & coordination of complex biologic functions
Take Home MessageTake Home Message