Receptors linked to kinases and nuclear receptors

andreatong18
Flashcards by andreatong18, updated more than 1 year ago
andreatong18
Created by andreatong18 over 7 years ago
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Pharmacology Flashcards on Receptors linked to kinases and nuclear receptors, created by andreatong18 on 20/10/2013.

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Receptor Enzymes - Extracellular surface. - Intracellular surface. - insulin receptor is prototype.
Insulin Receptor - Insulin regulates: i) metabolism, ii) gene expression. - Extracellular insulin signal -> insulin receptor -> insulin-sensitive metabolic enzymes -> nucleus -> gene transcription.
Structure of Kinase-Linked Receptor - 2 identical a-chains. - 2 identical B-subunits. - Insulin binds at a. - PK activity on B-subunit. - PK activity transfers phosphoryl group from ATP to OH of tyrosine residues on terget proteins.
Sequence of Events # 1 - Insulin binds a-chain of receptor. - Tyrosine kinase activity of B-Subunit activated. - Each aB monomer phosphorylates tyrosine residues on the B-chain of its partner in the dimer. - Opens up active site -> tyrosine residues on other proteins can be phosphorylated.
Sequence of events # 2 - Insulin receptor substrate-1 is a target protein. - receptor phosphorylates IRS-1 on tyrosine residues. - A tyr-P residue in IRS-1 interacts with a protein called Grb2.
Sequence of events # 3 - Grb2 binds Sos. - Bound Sos catalyses replacement of bound GDP with GTP on a protein called RAS. - RAS-GTP can bind and activate a protein kinase -> Raf-1.
Sequence of events # 4 Raf-1 phosphorylates MEK. - MEK-P-P phosphorylates MAPK. - MAPK-P-P enters nucleus.
Sequence of events # 5 - Activate Elk1-P binds SRF. - Elk-P-SRF stimulates transcription and translation of genes needed for cell division.
What else does phosphorylated IRS-1 do? - IRS-1-P binds PI-3 kinase. - Activate PI-3K phosphorylates phosphatidylinositol 4,5-biphosphate. - PIP3 binds another protein kinase.
# 2 - Bound PIP3- PKB phosphorylated by PKD1. - PBK can phosphorylate serine and threonine residues on target proteins. - GSK3 is active without phosphorylation.
# 3 active GSK3 phosphorylates glycogen synthase. - Non-phosphorylated GS -> active - Phosphorylated GS -> Inactive. - PKB phosphorylation of GSK3 prevents GSK3 phosphorylation of GS.
# 4 - Non-phosphorylated GS continues to convert glucose into glycogen. - PKB also triggers glucose transporter movement. - GluT4 moves from internal vesicles to plasma membranes. - Stimulation of blood glucose uptake.
SH2 Domain Proteins - Src homology 2. - Amino acid sequence of SH2 domains similar to a domain in another protein tyrosine kinase called Src. - SH2 domains found in other signalling proteins. All bind to tyr-P on another protein.
Receptor Kinases - One activated receptor can activate several IRS-1 molecules. - IRS-1 can activate any SH2-domain proteins.
Nuclear Receptors Bind to: - Steroids - Retinoids - Thyroid Hormones - Vitamin D
# 2 - Used by steroid and thyroid hormones. - Are stimulated in nucleus. - active receptor stimulates gene transcription -> specific proteins are produced. -> proteins induce cellular effects.
# 3 - All nuclear receptors have a DNA-binding domain. - Ligand binding domain is downstream from DNA-binding domain. - Upstream from DNA-binding domain is a region that controls gene transcription.
# 4 - Steroid binds receptor - dimers bind to hormone response elements of nuclear DNA. - HREs are 200 bp upstream from target genes. - Response is an increase in RNA polymerase activity -> extra mRNA produced.
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