test 3 Flashcards
- What are agonists?
Activators of the cell response.
What are antagonists?
Molecules that block the response of agonists.
What are inverse agonists?
Blocks agonist and can turn off basal response.
What are the major classes of cell signaling systems?
Ionotropic: receptor is a ligand gated ion channel. Ex: nicotinic acetylcholine receptor.
Metabotropic: receptor is an allosterically regulated non-classical enzyme. Ex: G-protein coupled receptor.
Enzyme-Linked Receptor: receptor is a classical enzyme.
Nuclear: receptor is an allosterically regulated transcription factor. Ex: steroid receptors.
What are agonists of the TRPM8 channel?
Menthol, icilin
What are second messengers?
Small ions or molecules that are either released into the cytoplasm or synthesized in the cytoplasm in response to activation of a signaling receptor.
GPCR/G-protein cycle [STEPS, 3]
1)Ligand binding to GPCR causes G(beta-gamma)(GDP) ti dissociate from G(alpha-beta-gamma)(GDP) and GDP gets swapped for GTP
2)G(alpha)(GTP) is not active and hydrolysis of GTP can occur
3)Once GTP is cleaved into GDP, GDP is stuck, G(alpha) cannot serve as an allosteric regulator and G(beta-gamma) associates reforming the initial inactive complex
G alpha s pathway [ANDREGERNIC PATHWAY] ([How does it work; explanation of all the steps on slide 51]
1) Epinephrine binding to GPCR results in swap of GDP to GTP and release of G(beta-gamma)
2) G(alpha)GTP can now drift to adenylate cyclase and activate it
3)Cyclic amp is made by adenylate cyclase
4) 4 cAMP bidns to the 2 R subunits of adenylate cyclase (2 cAMP each) (tetramer 2 Regulatory(r) 2 catalytic ( C)), R subunits fall off
5) C subunits enter and phosphorylate CREB which binds to DNA and activates transcription
Sometimes: there can be another GPCR that activates Galpha i (Galphai and Galphas can both bind to adenylate cyclase regulating the amount of cAMP made)
What motif does CREB use to bind to DNA?
Leucine zipper
Gq (inositol pathway)
1) GPCR activates G protein when a ligand binds
2) G(alpha)GTP drifts to the phospholipase C, which cleaves PIP2 into its head group (IP3) and diaacyl glycerol. Diacyl glycerol activates protein kinase C
3) head group (IP3) binds to the IP-3 gated calcium channel and calcium flows into the cytosol. Calciums further activate protein kinase C
homologous desensitization of GPCRs?
pathway involves two additional proteins GRKs (G-receptor kinases and arrestins).
GRKs only phosphorylate activated GPCRs.
GENERAL RTK mechanism
1)Ligand binds and activates the RTK. Dimerizaation of the RTK is also caused by the ligand binding
2)Autophosphorylation
3)Proteins can associate (SH2 domain can bind to the phosphotyrosine residue)
AN EGFR PATHWAY (9 STEPS)
1)Pair of EGF binds to the receptor
2)Adaptor binds to the rtk (GRB2)
3)SOS (GEF) binds to the adaptor
4) Inactive G protein RAS (not heterotrimeric) binds and SOS replaces the GDP. A protein GAP increases the catalytic rate of RAS (gtp hydrolysis)
5) Raf (ser/thr kinase) binds to Ras(GDP) and Ras(GDP) brings Raf to the membrane thus activating it
6) Raf activates SRC (membrane associated tyrosine kinase) on the membrane and Raf gets phosphorylated, which further activates Raf
7) Mek phosphorylated by Raf
8) Erk phosphorylated by Mek
9) Phosphorylated Erk can enter the nucleus and phosphorylate transcription factors
Note: Both RASGAP and phosphatases strip phosphate groups off of phosphorlyated proteins, turning the signaling pathway off
AN INSULIN PATHWAY (5 steps)
1) Insulin binds and results in the cross phosphorylation of the tetramer in the intracellular domains. The insulin receptor is a tetramer unlike the dimerized Epidermal growth factor receptor.
2) Insulin receptor substrate (IRS)binds to the phosphotyrosine
3) AFter binding, the IRS becomes phosphorylated. Phosphorylated IRS bidns and activates phosphoionsitide-3-kinase (PI-3 Kinase which takes PIP 2 and makes it PIP 3)
4) PDK1 binds to the PIP 3 through a plekstrin homology domain
5) Akt is phosphorylated by PDK1 and dissociates from the membrane and phosphorylates other substrates.
Results: up-regulation of the GLUT4 transporter, and the activation of glycogen synthase
Nitric Oxide Signaling (
1) Nitric oxide released by nitric oxide synthase binds to the heme which causes a conformation change activaating guanylyl cyclasae
2) cGMP is made (phosphodiesterase 5 [PDE5] cleaves cGMP)
3) cGMP activates protein kinase G
Viagra works by inhibiting phosphodiesterase 5, which allows cGMP to persists for longer.
