Cinderella Aquino Cell Bio Review Feb. 9, 2010. Signal transduction Signal transduction: Detection...
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Transcript of Cinderella Aquino Cell Bio Review Feb. 9, 2010. Signal transduction Signal transduction: Detection...
Cinderella Aquino
Cell Bio Review
Feb. 9, 2010
Signal transduction
Signal transduction: Detection of specific signals at the cell surface and the mechanism by which such signals are transmitted into the cell’s interior, resulting in changes in cell behavior and/or gene expression
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Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)
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Different types of chemical signals can be received by cells
Ligand: substance that binds to a specific receptor, thereby initiating the particular event or series of events for which that receptor is responsible
Primary messenger: A molecule that binds to a receptor, thereby beginning the process of transmitting a signal to the cell
Second messenger: any of several substances, including cyclic AMP, calcium ions, inositol triphosphate, and diacylglycerol, that transmit signals from extracellular signaling ligands to the cell interior
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The binding of extracellular signal molecules to either cell-surface or intracellular receptors Most signal molecules are
hydrophilic and are therefore unable to cross the target cell’s plasma membrane directly; instead, they bind to cell-surface receptors, which in turn generate signal inside the target cell
Some small signal molecules, by contrast, diffuse across the plasma membrane and bind to receptor proteins inside the target cell- either in the cytosol or in the nucleus. Many of these small signal molecules
are hydrophobic and nearly insoluble in aqueous solutions; they are therefore transported in the bloodstream and other extracellular fluids bound to carrier proteins, from which they dissociate before entering the target cell.
G-protein signaling G-protein-coupled receptors
(also called Heptahelical receptors) Act by indirectly regulating the activity of a separate
plasma-membrane-bound target protein, which is generally either an enzyme or an ion channel
A trimeric GTP-binding protein mediates the interaction between the activated receptor and this target protein
Remember the whole G-protein being active when bound to GTP and inactive when bound to GDP?
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Gs signaling
http://www.youtube.com/watch?v=V_0EcUr_txk
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Cyclic AMP is a second messenger used by one class of G proteins
Adenylyl cyclase (found associated with plasma membrane) forms cyclic AMP (cAMP) from cytosolic ATP
Gs signaling pathway activates adenylyl cyclase Phosphodiesterase degrades cAMP
Table 15-1 Molecular Biology of the Cell (© Garland Science 2008)
Cyclic AMP is a second messenger used by one class of G proteins cAMP-dependent kinase or protein kinase
A (PKA)PKA is a serine/threonine kinasePKA has two regulatory subunits and two catalytic
subunits. When cAMP binds to PKA, the regulatory subunits disassociates from catalytic subunits
The cAMP pathways are important for regulating glycogen metabolism, heart contraction, blood clotting and secretion of salts and water in the gut
http://www.youtube.com/watch?v=iGb93jCKVXs&feature=related
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Intracellular effects of the cAMP pathway: Control of glycogen degradation Epinephrine binds -Adrenergic receptor
Epinephrine is a key hormone in the fight-flight response Gs protein binds GTP, dissociates from other subunits Activated Gs binds and activates adenylate cyclase Adenylate cyclase produces cAMP from ATP PKA binds cAMP and becomes activated PKA phosphorylates and activates Phosphorylase Kinase Phosphorylase Kinase phosphorylates phosphorylase b into the
active phosphorylase a form Phosphorylase a catalyzes the phosphorolytic cleavage of
glycogen into glucose-1-phosphate Meanwhile, the enzyme system responsible for glycogen
synthesis is inactivated by cAMP pathway. PKA also phosphorylates the enzyme glycogen synthase and inactivates it
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Cyclic AMP-inducible gene expression The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein), leading to expression of cAMP-inducible genes.
PKA Also Phosphorylates Transcription FactorsPKA Also Phosphorylates Transcription Factors
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Cholera toxin poisoningdisrupts normal Gs protein signaling Cholera toxin alters secretion of salts and fluid in the intestine, which is
normally regulated by hormones that act through the Gs to alter intracellular cAMP levels. A portion of the cholera toxin is an enzyme that chemically modifies Gs, so that it can no longer hydrolyze GTP. Thus cAMP levels stay high and cells stimulate to secrete salts and water
The Details Cholera A toxin is absorbed into mucosal cells, where it is processed and
complexed with ARF (ADP-ribosylation factor), a small G-protein that is normally involved with vesicular transport.
Cholera A toxin is an NAD-glycohydrolase, which cleaves NAD and transfers the ADP ribose portion to other proteins.
It ADP-ribosylates the Gs subunit of heterotrimeric G-proteins, thereby inhibiting their GTPase activity.
As a consequence, they remain actively bound to adenylyl cyclase, resulting in increased production of cAMP.
The CFTR channel is activated, resulting in secretion of chloride ion and Na+ ion into the intestinal lumen.
The ion secretion is followed by loss of water, resulting in vomiting and watery diarrhea
Methylxanthines Methylxanthines:
caffeine from coffee and teatheophylline from tea theobromine from chocolate
Two modes of action:The principal mode of action of
caffeine is as an antagonist of adenosine receptors ○ The caffeine molecule is structurally similar
to adenosine
Methylxanthines are also cAMP phosphodiesterase inhibitors
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Gi Signaling Gi signaling can inhibit Adenylyl
cyclase activity by the G subunit Gi subunits act mainly by
regulating ion channels For example stimulation of muscarinic
acetylcholine receptors by acetylcholine released by the vagus nerve, results in the subunits binding to K+ channels in the heart muscle plasma membrane and opening them.
Whooping cough (pertussis toxin) The inhibitory protein Gi is inactivated
by pertussis toxin, Gi can no longer inhibit adenylyl cyclases
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Gq Signaling Many G proteins use inositol triphosphate and diglycerol as
second messengers Phospholipase C cleaves PIP2 into inositol triphosphate and DAG
The inositol-phospholipid-calcium pathway Ligand binds to receptor Gq is activated Gq then activates phospholipase C PIP2 is cleaved into InsP3 and DAG InsP3 binds to InsP3 receptor (ligand-gated calcium channel) in ER Calcium is released into cytosol and binds calmodulin and modulates other
pathways Meanwhile DAG activates protein kinase C (PKC) PKC then stimulates other pathways
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Gq Signaling PathwayGq Signaling Pathway
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The calcium-calmodulin complex In the cytosol, calcium binds to proteins like
calmodulin. Calmodulin is one of the most important
calcium-binding proteins in the cell and can constitute as much as 1% of the total protein mass.
When calmodulin is activated after binding calcium, it targets and regulates kinases and phosphatases
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Nitric Oxide couples G protein-linked receptor stimulation in endothelial cells to relaxation of smooth muscle cells in blood vessels Nitric Oxide (NO) produced by NO synthase, which
converts amino acid arginine to NO and citrulline NO stimulates guanylyl cyclase to make cGMP
Figure 15-12b Molecular Biology of the Cell (© Garland Science 2008)
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NO, erectile dysfunction and angina pectoris
Nitroglycerin for angina to release constricted coronary arteries. Glycerol trinitrate decomposes to NO, which activates a
guanylyl cyclase.This will relax arterial smooth muscle cells
Viagra (sildenafil): an inhibitor of cGMP-specific phosphodiesterase (breakdown of cGMP)Nitric Oxide released by the neurons in the penis results in the
blood vessel dilation responsible for penile erection. Viagra helps maintain elevated cGMP in erectile tissue, this
pathway is stimulated for a longer time period following NO release.
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Prostaglandins: typically activate G protein receptor
Prostaglandins such as thromboxane A (TXA2) can stimulate Gq signaling pathways
Prostaglandins are synthesized from arachidonic acid.Cyclooxygenases are key enzyme in the pathway
○ Aspirin blocks cyclooxygenases, thereby inhibiting synthesis of thromboxane A2 and other prostaglandins form arachidonic acid
○ Aspirin significantly reduces incidence of heart attacks by reducing blood clots
Key points Signal transduction is important! 3 major G protein pathways: Gs, Gi, Gq
Which is involved with cAMP production and glycogen breakdown?
Which is involved with Viagra?Which is affected by pertussis toxin? Cholera?
Caffeine?Which involves the cleavage of PIP2? What
molecules does PIP2 break down to?Which causes release of calcium?What causes the activation of PKA? PKC? PKG?
What do those do? Huh?