Lecture 3 Flashcards
Signal Transduction
Transmission/amplification
sorting and directing
integration
adaptation/modulation
4 Types of Cell Signaling
Autocrine
Juxtacrine
Paracrine
Endocrine
Autocrine Signaling
Cell targets itself
Juxtacrine Signaling
Acts on cells within close proximity that are connected by gap junctions. I.E. Cardiac muscle cells connected by intercalated discs
Paracrine Signaling
Acts on nearby cell, but ligands are secreted into cytoplasm and travel short distance to target cell
Endocrine Signaling
Ligands secreted into blood stream where they travel to target cell
Types of Signaling Pathway Receptors
Lipophilic ligand (doesn’t need receptor)
Transporter (water soluble ligands)
Ion channel (water soluble ligands)
GPCR (water soluble ligands)
Enzyme linked receptor (water soluble ligands)
Membrane receptors
Receptors are the detectors and initial amplifiers
when the receptor binds a ligand the receptor undergoes a conformational change which initiates signal transmission
Ion Channels
LIgand activated
GPCR-linked
2nd messenger activated
Kinases
Add phosphate to a molecule
can either activate or inactivate a protein
Phosphtases
take a phosphate away (ase)
Receptor Kinsases/Phosphotases
mostly used in growth/survival signaling.
most ligands are some type of growth factor (including growth hormone)
Main way things are turned off and on
Heterotrimeric G-Protein Coupled Receptors
HCPCR
HGPCR
2/3 of all ABX work through these receptors
Human genome project has identified about 500 HGPCRs
Ligand binds HBPCR > activation of G protein > activates 2nd messenger proteins and or activates ion channels
Almost like having kinase/phosphatase in the same unit.
Has alpha, gamma, and beta subunits.
Active subunit of HGPCRs?
alpha subunit
(most HCPCRs work through alpha subunit)
GEF
Guanine exchange factor
takes phosphate from GTP and adds phosphate to GDP on alpha subunit to activate it
GAP
GTPase activating protein (RGS protein)
takes phosphate away from alpha subunit of g protein inactivating it
Has both GEF and GAP?? (I will clarify this on Friday)
HGPCR Pathway Overview
Ligand binds receptor
ligand receptor complex activates G-protein (g protein binds GTP)
G protein disassociates from the complex
Alpha/beta/gamma subunits disassociate and interact with their
effector proteins
Hydrolysis of GTP by RGS inactivates the alpha subunit and promotes reassembly of the trimer (alpha/beta/gamma subunit)
Types of G alpha Proteins
Gs
Gi
Gq
Differential effects of GPCRs
Different tissues have different receptors, response depends on the type of receptor, and which 2nd messenger molecules are activated
Gs Protein
Activated by: Epi, NorEpi, histamine, glucagon, ACTH, LH, FSH, TSH, and more
Gi Proteins
Activated by: NorEpi, prostaglandins, opiates, angiotensin, many peptides
Gq Protein
Activated by: Acetylcholine, Epi
Gs Signaling Pathway
Increase cAMP
increase Ca++ influx
Gi Signaling Pathway
Decrease cAMP
Increase IP3 and CA++
Gq Signaling Pathway
Increase: IP3, DAG, Ca++
Polarize membrane
G Protein Acting by Adenylyl Cyclase
Receptor linked to Gs activated adenylyl cyclase
converts ATP to cAMP which acts as small intracellular transporter
(Gs think stimulation of cAMP)
(cAMP is also most widely used 2nd messenger)
activates cAMP dependent protein kinase (PKA) (4cAMP to 1 PKA)
PKA phosphorylates many proteins leading to cell response
A cellular signaling pathway that leads to increase in cAMP must occur through which G alpha protein?
Gs. Any increase of cAMP is modulated by Gs.
G-Protein acting via phosphodiesterase (PDE)
Receptor linked to Gi activates PDE,
PDE brakes the ester bond of cyclic nucleotides (cAMP) leaving monophosphate nucleotides (AMP) without signaling function (can’t activate PKA).
Gi think inhibitory
Basically: PDE breaks down cAMP
G protein action via PDE Example (don’t need to know for test, only to help understand the concept)
In vascular smooth muscle:
Gs> ^cAMP > inhibits MLCK > prevents contraction > causes vasodilation
Gi > decrase cAMP > inhibit inhibition of MLCK > prevent relaxation > cause contraction
G-Protein acting via Phospholipase
Receptor linked to Gq activates membrane bound enzyme phospholipase C (PLC)
PLC converts membrane phospholipid into 2nd messengers inositol triphosphate (IP3) and diacylglycerol (DAG)
IP3 bind receptor on SR causing release of Ca++
DAG binds and partially activates protein kinase C (PKC)
Ca++ triggers many cellular events including the full activation of PKC
Signaling via Lipid Molecules
Phospholipase A2 (PLA2) breaks down membrane phospholipids into arachidonic acid.
Arachidonic acid > lipoxygenase > leukotrines
Arachidonic acid > cycloxygenases (COX1/COX2) > prostaglandins, prostacylcines, & thomboxanes
*we take aspirin or NSAIDs to block cycloxygenase activity
Effects of Leukotrines
vasoconstriction
brochnospasm
^ vascular permeability
Effects of Prostaglandins / Prostacyclins
vasodilation
^ vascular permeability
inhibit platelet aggregation (prostacyclins)
Effects of thromboxanes
vasoconstriction
platelet aggregation
Thromboxanes occur latter on in the inflammation process
Predominant Inflammatory Signaling molecules
lipoxygenase
cycloxygenase
leukotrienes
prostaglandins
prostacyclins
thromboxanes
Signaling via Gases
Nitric oxide (NO) synthesized by the enzymatic (NOS) degradation of arginine > 2nd messenger guanylyl cyclase > activation of cGMP > PKG signals (cGMP > PKG pathway is the same as the cAMP > PKA pathway)
Remember: gasses diffuse across membranes. NO is acting as ligand
NO is the primary signaling gas
Why is vasodilation controlled by gas signaling?
There is no parasympathetic innervation of vascular smooth muscle, so vasodilation is entirely mediated by NO.
3 ways NO is produced
- Produced by neurons (nNOS). Acts as neurotransmitter and neuromodulator in the brain.
- Produced by endothelial cells (eNOS): inhibits platelet aggregation and leukocyte adhesion, causes vasodilation
- Inducible form (iNOS): produced by wide range of tissues; induced by pro-inflammatory cytokines producing huge amounts of NO
Lipophilic Ligands
Can pass through cell membrane on their own
intracellular receptors are usually in the nuclear membrane, slow metabotropic receptors.
Affect transcription/translation of proteins.
Many hormones and drugs work this way.
This pathway works from bottom of cell up, unlike the other signaling pathways.
Signal Modulation
We can modulate signaling events over time by changing lots of different things. I.e number of receptors, ligand concentration, ligand specificity, receptor affinity.
An example: in opioid abuse receptors become less responsive over time
How can single ligand I.E (NE) elicit opposite responses in identical tissues at different locations simultaneously?
some tissues have both beta and alpha receptors, the [NE} determines which receptors are activated.
Target response depends on the target receptors and ligand concentration.
Agonist vs Antagonist
Agonist: mimics normal response
Antagonist: binding inhibits response. Two types, competitive and allosteric (noncompetitive) inhibition.
Signal Transduction is Adaptive
Over time strength of stimuli and increase or decrease.
Multiple overlapping adaptive mechanisms dependent on strength and duration of stimulus.
