Signal Transduction Pt. I Flashcards
what do the terms Endocrines, Paracrines and Autocrines mean
Endocrine -Exerts actions on specific targets cell which are far away
Paracrine - Action performed on nearby cells
Autocrine - a messenger that actions on the cell that secretes it
what are the basic characteristics of signal transduction
The basics include the fact that first a signal is detected at the surface of the cell.
Transduction is the mechanism by which the cell interrupts that signal and changes its behavior or gene expression
Where receptors for hydrophobic and hydrophilic ligand are usually found
Hydrophilic- On the cell suface
Hydrophobic - intracellular
what is nuclear initiated steroid receptor signaling
Slower, involves changes in gene expression
Includes steroid hormones, thyroid hormones, retinoic acid and Vit D
Receptors are transcription factors
Bind to the DNA promoter elements in genes and alter gene expression
ZINC FINGER = steroid hormone receptors
Hormones need to be transported in the blood bound to carrier proteins
What is membrane initiated signaling
Faster, including activation of G proteins and stimulation of protein kinases
Localized to membrane caveolae
Found either facing the outer surface of the plasma membrane or facing the cytosolic side tethered to a scaffolding protein
What are the modes of action of aromatase inhibitors
Used in treatment of estrogen-responsive breast cancer in POSTmenopausal women
they reduce the estrogen level significantly and remove the main source of the growth stimulation from estrogen-responsive tumors
What is the mode of action of Tamoxifen
works by blocking estrogen receptors in the breast there by inhibiting estrogen dependent growth of tumors
Use in PREmenopausal women
what is the Gs pathway
Ligand binds to receptor (hetrotrimeric Gs protein complex)
Complex becomes active and the α subunit binds GTP and dissociates
The α subunit binds and activates adenylyl cyclase
Adenylyl cyclase synthesizes cAMP from ATP
Cyclic AMP binds to 2 regulatory subunits of Protein Kinase A
The 2 catalytic subunits are set free to phosphorylate protein targets
what is the Gq pathway
Ligand binds to receptor
Gq is activated
Gq then activates phospholipase C-b
PIP2 is cleaved into InsP3 and DAG by PLC-b
InsP3 binds to InsP3 receptor 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
how do Methylxanathines (caffeine and theophylline) mediate their effects
the principal mode of action of caffeine is as an antagonist of Adenosine receptors becuase they are structurally similar to adenosine
are also cAMP phosphodiesterase inhibitors
how does epinephrine binding to receptors lead to glycogen breakdown
- Epinephrine binds to ß adrenergic receptor
- Gs protein binds GTP, and dissociates from the other subunits
- Activated Gs binds and activates adenylate cyclase
- Adenylate cyclase produces cAMP from ATP
- PKA binds cAMP and becomes activated
- PKA phosphorylates and actives 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
How does glucagon signal cells
Glucagon binds to high-affinity G protein-coupled receptors on hepatocytes and stimulates Gs signaling
how does PKA phosphorylate transcription factors
•The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB
This leads to expression of cAMP-inducible genes
how does cholera toxin poisoning disrupts Gs signaling
Cholera A toxin is absorbed into the mucosal cells
It is processed and complexed with ARF (ADP-ribosylation factor, normally involved with vesicular transport)
Cholera A toxin is an NAD-glycohydrolase and thus cleaves NAD and transfers the ADP ribose portion to other proteins
It ADP-ribosylates the Gαs subunit of heterotrimeric G-proteins
This inhibits GTPase activity
As a result, the complex remains actively bound to adenylyl cyclase resulting in INCREASED cAMP
The CFTR channel is activated
This results in the secretion of Cl- and Na+ into the intestinal lumen
The ion secretion is followed by a loss of water
This leading to vomiting and diarrhea
what is the general role of protein phosphatases in signaling
terminates responses initiated by receptor activation of protein kinases
how are odorant receptors involved in G-linked couple receptors
- Receptors stimulate adenylyl cyclase, leading to an increase in cAMP
- cAMP binds to and opens Na+ channels in the plasma membrane
- Leading to initiation of nerve impulse
What is Gi signaling
- Inhibits Adenylyl cyclase activity by the subunit by the Gα subunit
- Gi ßγ subunits act mainly by regulating ion channels
How is Transducin (Gt) signaling involved with photoreception
- Rhodopsin is activated when light is absorbed by the associated small molecule retinal
- Rhodopsin then activates G protein Transducin (Gt)
- This leads to decreased levels of cGMP
- cGMP levels are translated to nerve impulses by a direct effect of cGMP on ion channels
how is Gq signaling involved with platelet activation
•ADP released from damaged cells activates Gq receptors
•This activates PCLß
•PCLß cleave PIP2 into IP3 and DAG
•IP3 binds and opens calcium channels associated with endoplasmic reticulum
•The inositol trisphosphate gated calcium channel is a calcium-selective channel in the membrane of the endoplasmic reticulum.
An increase of cytosolic calcium concentration in platelets makes them sticky, initiating blood clotting.
what are calmodulin functions during calcium signaling
•When calmodulin is activated after binding calcium, it targets and regulates kinases and phosphatases
what is Malignant Hyperthermia
Autosomal Dominant Mutation in Ryanodine Receptor 1 Pt. develops life threatening injuries after recieving anesthetics Symptoms Increased muscle rigidity elevation of body temp rhabomyolysis
how does acetylcholine stimulation of endothelial cell to smooth muscle cell lead to smooth muscle relaxation
- Acetylcholine binds to heptahelical receptor and triggers Gq signaling in the endothelial cells
- Calcium is released into the cytoplasm from the sER
- Calcium binds calmodulin
- Calmodulin activates Nitric Oxide synthases
- Nitric Oxide synthase creates NO and citrulline from Arginine
- NO diffuses out of the endothelial cells and into the smooth muscle cell
- NO binds and activates Guanylyl cyclase
- Guanylyl cyclase synthesizes cGMP from GTP
- cGMP activates Protein Kinase G resulting in smooth muscle relaxation
Must know how nitroglycerin and Viagra effect NO and cGMP signaling
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.
Know how carbon monoxide acts a signaling molecule
- Carbon monoxide (CO), also functions as a signaling molecule in the nervous system.
- It acts similarly to NO as a neurotransmitter and mediator of blood vessel dilation.
- CO can stimulate guanylate cyclase, which also represents the major physiological target of CO signaling
what receptors do prostaglandins typically activate
G protein receptors
