8/15/17 Flashcards
Signal transduction
The processing of extra cellular signals to effect a change in the internal workings of a cell
3 Major classes of second messengers
Cyclic nucleotides: cAMP, cGMP
Inositol triphosphate and diacylglycerol
Ca2+ ions
Why different cells respond differently to the same signal
Difference in receptor structure
Difference in internal signaling pathway
Cholinergic neuron
Release acetylcholine that binds to acetylcholine receptors on skeletal muscle cells
Myasthenia Gravis
Autoimmune disease that causes muscle weakness and fatigue
Autoantibodies bind to ACh receptors, block signaling, receptors internalized and degraded
Treat by using acetylcholinesterase inhibitors, slow ACh breakdown to raise ACh conc. to compensate for the lower amount of receptors
Speed of extracellular signal effects
Immediate cell modification: like change in cell shape/activity, caused by changes in protein activity like phosphorylation
Long term changes:
Ike change in growth rate or differentiation, changes in gene expression and protein synthesis
G Protein-Coupled Receptors
Extra cellular ligand binding domain
Transmembrane domain that crosses plasma membrane 7 times
Intracellular domain that binds G-protein
G-proteins are enzymes that are active when bound to GTP, inactive when bound to GDP
Activation of G-proteins
Ligand binding to the receptor causes conformational changes that allow the alpha subunit of the G-protein to exchange GDP for GTP
The alpha (still bound to GTP) and beta/gamma subunit dissociate from the complex to move on and activate OR inhibit a target protein
G-protein structure
Hydrophilic but alpha and gamma subunits are lipid linked to the cell membrane
Beta subunit is bound only to the gamma subunit
Enzyme-linked receptors
Produce long term effects on the cell like cell growth, differentiation, proliferation, or survival
Signal molecules called growth factors
Tyrosine kinases
Single-pass reads,embrace protein with an extracellular receptor and an intracellular tyrosine kinase domain
Typically dimerized by ligand binding
Binding of growth factor has conformational change that activates cross phosphorylation
SH2 domain containing proteins bind to the phisphorylated Tyrs, some are only for structure and are called adaptors, others are REGULATORY molecules like kinases or GTP-binding proteins
Ion channel receptors
Transduction of neural signals
Neurotransmitters bind and open/close ion channel
Intracellular receptors
Small, hydrophobic molecules travel in extracellular fluid attached to a carrier protein
Dissociate from carrier protein to diffuse across plasma membrane
Captured by intracellular receptor and shuttled to nucleus where they affect gene expression
Steroid hormones, thyroid hormones, and retinoids
Gases as signaling molecules
ACh binds to an endothelial cell receptor and activates Nitric Oxide Synthase that makes NO from arginine
NO diffuses across plasma membrane to neighboring cells and binds to Guanylate Cyclase to produce cGMP
Increased cGMP results in relaxation of smooth muscle cells
Vasodilation
NO has localized (paracrine) effects
NO causes the smooth muscle cells within blood vessels to relax, creates vasodilation
Nitroglycerin broken down to NO, treats angina or inadequate blood flow to the heart
NO and cGMP on blood pressure
Vasodilation results in lower blood pressure
fatal if combine with other drugs that activate this pathway like those for pulmonary hypertension
Pulmonary hypertension: narrowing of lung vasculature with increased blood pressure, creates shortness of breath and swelling of hands/feet
Viagra is a cGMP phosphodiesterase inhibitor
cAMP production and degradation
Adenylate cyclase, regulated by the G-protein alpha subunit (Gs stimulates and Gi inhibits)
cAMP phosphodiesterase, is constantly active
cAMP Pathway
Stimulation of adenylyl cyclase produces cAMP
cAMP activates protein kinase A (PKA)
PKA phosphorylates proteins in cytosol or go to nucleus to activate proteins for gene transcription
Clinical examples of cAMP
- Epinephrine and norepinephrine bind to adrenergic receptors (G-protein coupled receptor)
Increased heart rate, block receptors to treat hypertension (beta blockers are agonists of adrenergic receptors)
- Cholera toxin ADP-ribosylates the alpha subunit of Gs proteins so can’t hydrolyze GTP to GDP and stay always active
High cAMP causes flow of water into intestinal lumen, killer diarrhea
PI and Ca2+ signaling
Alpha subunit of a G protein activates phospholipase C
Breaks PIP2 into IP3 and diacylglycerol
IP3 opens ion channel of ER lumen, Ca2+ rises in the cytosol
Diacylglycerol activates (along with Ca2+) Protein Kinase C, which phosphorylates other proteins into activation
Ras
GTP binding protein downstream of receptor tyrosine kinases, activated by almost all RTK
Activates the MAP kinase pathway, are activated by cell stress so help with cell survival
Ras-activating protein binds to adaptor protein of RTK and then switches GDP on Ras protein for a GTP
Active Ras protein activates MAP-K-K-K, which phosphorylates MAP-K-K, which gets MAP-K to phosphorylates other proteins and gene regulatory proteins
Cause changes in protein activity and changes in gene expression
Ras clinical
Mutations in Ras present in 30% of all cancers
Mutant Ras genes are one type of oncogenes
PI-3 Kinase Pathway
Ras and other signaling molecules activate PI-3 kinase which phosphorylates phosphatidylinositol
Phosphorylated inositol stay attached to the membrane to activate other signaling molecules
Stimulate cell growth and survival
JAK-STAT pathway
Cytokine receptor that have associated cytoplasmic kinases associated with it (JAK) to do Tyr kinase activity, cytokine binding leads to cross phosphorylation of the receptor
STAT gene regulatory proteins bind to the phosphorylated cytokine receptor and are activated
Activated STATs dimerize to travel to the nucleus to affect gene expression
Important for immunity and inflammation
Examples of JAK-STAT signaling
Gamma-interferon: activates macrophage
Alpha-interferon: up cell resistance to viral infection
Erythropoietin: stimulates erythrocyte production
JAK inhibitors for inflammatory diseases like rheumatoid arthritis and psoriasis
TGF-Beta pathway
Play a role in development (Transforming growth factor)
TGF-Beta binds to the receptor and the receptor phosphorylates itself through a Ser/Thr domain
Activated receptor binds SMAD and phosphorylates it
Activated SMAD dissociates from the receptor and binds to a different SMAD
Travel to the nucleus and affect gene expression
G-protein linked receptors in heart function
Beta-adrenergic receptor regulate contractile the of heart muscle, bind epi and norepinephrine
Activated alpha subunit activates adenylyl cyclase and PKA
PKA phosphorylates cytoplasmic targets that regulate contractility, relaxation, and heart rate
A G-protein receptor kinase (GRK2) phosphorylates overactive beta adrenergic receptors, Beta-arrestin binds
G-protein linked receptors desensitization
Chronic stress, certain disease states make high levels of epi and norepinephrine, prevents continual receptor activation
Downregulation: decrease receptor synthesis or increase degradation (slow mechanism)
Sequestration: internalization of receptor (rapid mechanism)
Inactivation: phosphorylation of the receptor so the G-protein can’t associate (rapid mechanism)
G-protein linked receptor inactivation
G-protein linked receptor kinase phosphorylates an activated receptor
Arrestin binds to the phosphorylated receptor, the receptor is desensitized
Insulin receptor signaling
Insulin receptor is pre-dimerized with Cys residues linking alpha and beta subunits, is a Tyr kinase receptor
Insulin binding activates MAP kinase and PI-3K pathways
MAP kinase: Elliot growth and proliferation
PI-3K: cell survival and proliferation, make macromolecules, cause GLUT-4 to be inserted into the plasma membrane
PI-3K pathway in insulin signaling
PI-3K converts PIP2 to PIP3 to activate a kinase called AKT
AKt has downstream effects like increased glucose metabolism
PTEN (a phosphatase) inactivates this pathway
PI-3K signaling important in cancer
