mechanism of hormone action. hormones three types –proteins glycoproteins small pepstides large...
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Mechanism of hormone action
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Hormones
• Three types– Proteins
• Glycoproteins• Small pepstides• Large proteins
– Lipids• Cholesterol derivatives• Eicosanoids
– Amino acid derivatives
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• Hormones– Innate by themselves– Require mediation
• Receptors– Binding sites for a hormone
• Very specific
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Hormone receptors
• Two types– Transmembrane– Intracellular/nuclear– Proteins regardless of the type
• Interaction between a hormone and a receptor– Initial step of hormone action
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Transmembrane receptors
• Protein hormones– Unable to pass through the plasma
membrane• Size• Charges
– Receptors must be located on the plasma membrane
• Extracellular domain for interaction with hormone• Intracellular signaling system
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Types of transmembrane receptors
• Receptors with multiple transmembrane domains– Seven trans-membrane domain receptor– No intrinsic enzymatic activity (C-terminus)
• Associated with intracellular proteins involved in signaling– G-proteins
– Modification of extracellular domain (hormone binding site, N-terminus)
• Glycosylation– Crucial for hormone binding
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• Trans-membrane domains (7)– Alpha-helix
• Hydrophobic amino acids
• Loops– Connect alpha helices
• May be linked by disulfide bridges (extracellular loop 1 and 2)
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• Intracellular/cytoplasmic domain– Palmitoylation of some cysteine residues
• Attachment of fatty acids• Fourth loop
– Site for phosphorylation
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• General structure of seven trans-membrane receptor– Variations
• Amino acid sequences– Variable length of N-terminus– Affects binding of ligand/hormone
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• Intracellular signaling– Generated when a hormone interacts with
extracellular domain of the receptor• Conformational change within the trans-membrane
helices• Exchange of GDP to GTP on the alpha-subunit of
G-protein complex– Activation of Gsubunit
• Dissociation of activated G from G-protein complex (
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• Second messengers– Cyclic nucleotides (cAMP and cGMP)
• cAMP– Widely used secondary messenger– Generated by adenyl cyclase
» Activated by activated Gsubunit of G-protein complex
• Activation of cyclic nucleotide-dependent protein kinases
– Protein kinase A (cAMP)
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• Secondary messengers– Amplification of hormonal signals
• Binding of hormone to the receptor• Activation of adenyl cyclase by activated G • Activation of protein kinase A by cAMP
– Rapid clearance and inactivation• Phosphodiesterases
– Inhibited by methylxanthines (caffeine, theophylline, and theobromine)
• Phosphoprotein phosphatases
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• How do we know that cAMP is a secondary messenger?– Changes in production of cAMP after hormonal
treatment– Correlation between amount of cAMP being produced
and cellular response to the hormone– Inhibition of phosphodiesterase activity
• Presence of ligand but no effects
– Treatment with cAMP analogues/agonists• Similar response to that of hormone
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• Types of G-protein complex– Gsubunit (20 different types)
• Gs (stimulatory G• Gi (inhibitory G• Go (associated with orphan receptors in neurons)• Gt (transducin found in retina, activates cGMP-
specific phosphodiesterases)
– complex• 4 or more
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• Identification of specific G-protein complex associated with particular receptor– Structurally similar to each other– Use of pertusis toxin (bacterial toxin)
• Uncoupling of G-protein complex from the receptor– Gi is very susceptible
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• G-protein complex coupled with secondary messenger system other than cyclic nucleotides– Generated through phospholipid metabolism
• Inositol triphosphate (IP3)
• Diacylglycerol (DAG)• Arachidonic acid
– Activation of phospholipase C (PLC) by activated G
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• IP3– Water-soluble
• Stimulate release of Ca
• DAG– Binds to protein kinase C
• Activated by elevated Ca
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• Medical importance– 65 % of prescription drugs target G-protein
coupled receptors• Variety of ligands
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Other protein hormone receptors
• Transmembrane receptors with intrinsic tyrosine kinase activity– Receptor tyrosine kinase
• Receptors for insulin and many growth factors
• Transmembrane receptors with associated tyrosine kinases– Cytokine receptors
• Receptors for growth hormone and prolactin• No intrinsic kinase activity• Interaction between receptor and hormone causes
recruitment and activation of tyrosine kinases associated with receptor
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Receptor tyrosine kinase
• Approximately 100 receptor tyrosine kinases in human– Highly conserved
• Domains– Extracellular
• Hormone binding site
– Transmembrane– Intracellular/cytoplasmic
• Tyrosine kinase activity
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• 16 subfamilies– Based on extracellular domain– Variation on extracellular domain
• Interaction with variety of factors– EGF, PDGF, and insulin
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• Activation of receptor– Dimerization
• Dimeric ligand (two subunits)
– Each subunit binds to a receptor
• Two binding sites within a hormone
– One hormone interacts with two receptors
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• Activation of receptor– Pre-existence as a dimer
• Receptor is a dimer• Activated through interaction with ligand
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• Activation of receptor– Conformational changes in the kinase domain
• Accessible to the substrate
– Autophosphorylation of tyrosine residues (3 in insulin receptor)
• Activation loop• Triggers conformational changes
– ATP binding– Interaction with intracellular proteins– Phosphorylation of other proteins