2 Cell Sig And Sig Transduction Flashcards
What is the importance of cell signaling in intercellular communication?
No cell lives in isolation. Cell survival depends on an elaborate intercellular communication network that COORDINATES growth, dx, and metabolism.
What type of processes are regulated by cell-cell signaling?
- Metabolism
- Cell growth and division
- Cell movement
- Differentiation
- Development
- Processing of sensory information
Types of cell signaling and cellular signals
Types of Cell Signaling
- Direct Intercellular Communication (e.g. Gap junctions)
- Signaling by PM-bound molecules
- Receptor-mediated intercellular communication (CSR or Nuclear Receptors)
Types of cellular signals
- Physical - UV, light, mechanical, etc.
- Chemical - hormones, NTs, ATP, etc.
Differentiate the ff:
- Gap Junctions
- Juxtacrine signaling
- Paracrine signaling
- Autocrine signaling
- Synaptic signaling
- Endocrine signaling <3 <3 <3
- Gap Junctions - Allows ions and molecules to pass; made of connexins (six 4-pass connexons)
- Juxtacrine
- signaling molecule stays attached to the cell producing the signaling molecule.
- “contact-dependent signaling”
- impt: cell has the specific receptor
E.g. NK cells recognizing healthy cell of body - Paracrine
- Signaling molecule released into neighboring cells - Autocrine
- signaling molecule of producer affects the producing cell, itself
E.g. T helper cell producing IL-2 due to macrophage activity; IL-2 will affect TH cell - Synaptic
- paracrine-like because it’ll affect neighboring cells BUT makes use of NTs
- *only occurs between the cells with synapse
E.g. neuron and muscle controlled by neural activity - Endocrine signaling
- makes use of the bloodstream
- signaling molecule transported in long distances
Three steps in cell signaling
- Reception
- detection of signal - Transduction
- signal converted from extracellular to intracellular messages; conversion of a signal of some type from 1 physical form to another - Response
- converting specific signals from 1 form to another
Physiological responses to cell signaling
Cell divides or stops dividing, dx, commits suicide, kills, moves, alters metabolism, passes signals, etc.
Key components of a signaling pathway. Briefly describe each.
- Ligand (Agonist vs. Antagonist, Endogenous vs. Exogenous)
- Receptors (High affinity & specificity to ligand; can be cell membrane or intracellular: cytoplasmic/nuclear)
- Signal transduction proteins
- aka Intracellular signaling proteins
- converts external signal into intracellular signals
- may make use of 2nd messengers
- usually multiple steps; “domino principle” - 2nd messengers
- **mediate effects of 1st messengers - Effector protein
- **usually binds to a protein to regulate activity
Differentiate receptor molecule from receptor organ.
Receptor organ e.g. sense organs like organ of corti in the ear); The one in the signaling pathway is the receptor molecule.
Types of receptors based on location?
A. Cell-surface receptor
-usually has a hydrophilic ligand
B. Intracellular receptor
-usually has a small, hydrophobic ligand which can readily enter PM and nuclear membrane
Long-term effects are usually brought about by alterations in ____? Short term?
Long-term: gene expression
Short-term: protein function alteration
Differentiate Cell membrane vs. Intracellular Receptors based on:
- Type of receptor/Location
- Ligand
- Regulate what?
- Onset of effects
Cell Membrane:
- TM
- Hydrophilic
- Intracellular signaling pathways (2nd messengers)
- Faster
Intracellular
- Cytoplasmic or nuclear
- Hydrophobic (*small)
- Regulate gene expression
- Longer
Steroid receptors:
A. What happens when a ligand binds to the steroid receptor?
B. Effects of steroid hormones
C. Location
A. It becomes a TF which will bind to HREs
B. Genomic action (alter gene expression) and nongenomic (since some hormones have faster effects, the receptors may be within the cell membrane)
C. Inside and outside the cell
Cell-Membrane receptor types?
- Ionotropic/Ion-channel-linked receptors/Ligand-gated ion channel receptors
- GPCR
- Enzyme-linked receptors
>Catalytic receptors
>Cytokine receptors
Ionotropic receptors A. Other terms B. Characterize C. Type of transport D. Mechanism (translate what?) E. True or False. They cannot be regulated. F. True or False. They are involved in rapid synaptic signaling between electrically excitable cells. G. Type of Receptor
A. Ion-channel-linked receptors / Ligand-gated ion channel receptors
B. Composed of proteins with pore in the middle
C. Downhill; not coupled to energy
D. They translate a chemical signal to electrical signal!!!
E. False. They could be regulated by other ion channels. (E.g. Ca2+ concentration can trigger opening of Cl- ion channels).
F. True.
G. CMR
GPCR
A. Characterize.
B. Functions
C. Mechanism (general)
A. 7 pass TM protein
B. Nearly all human senses, behavior, mood, immune and nervous system regulation
C. Ligand binds -> activation of GPCR -> GTP displaces GDP from G-protein then Galpha subunit dissociated leaving the beta-gamma complex -> Galpha binds and activates target protein/s -> Galpha hydrolyzes GTP and dissociates from target protein -> Galpha with GDP will go back to the beta-gamma complex forming the inactive G-protein
Most abundant type of receptor in the cell?
Clue: Half of known drugs work directly/indirectly through this type of receptor
GPCRs
Can G-proteins activate ion channels? Explain.
Yes.
E.g. Muscarinic Ach binding -> G alpha dissociation from complex —> Gbeta-gamma opens K+ channels = decreases heart rate & contraction
E.g. Odorant binds to receptor —> Galpha + GTP dissoc from complex and stimulates adenylate cyclate —> increase cAMP —> increase cAMP-gated ion channel (enter Na+ and Ca2+) = depolarization and generation of action potential
The diversity of GPCR usually depends on?
Differentiate According to class, Associated Effector, 2nd messenger, and Receptor examples
Type of alpha subunit
E.g. Galphas, Galphai, Galphaq, G12,13alpha, Galpha olf
C: Galpha stimulatory
AE: Adenylyl cyclase
2M: cAMP (inc)
E.g. beta-adrenergic receptors; receptors for glucagon, vasopressin, and serotonin
C: Galpha inhibitory
AE: Adenylyl cyclase (but Gbeta-gamma is the activator e.g. K+ channel)
2M: cAMP (dec), change in membrane potential
E.g. alpha2-adrenergic, muscarinic Ach
C: Galpha olfactory
AE: Adenylyl cyclase
2M: cAMP (inc)
E.g. odorant receptors in nose
C: Galpha q
AE: PLC
2M: IP3, DAG (increased)
E.g. alpha1-adrenergic
C: Galpha 0
AE: PLC
2M: IP3, DAG (inc)
E.g. ACh receptor in endothelial cells
C: Galpha transducin
AE: cGMP phosphodiesterase
2M: cGMP (dec)
E.g. rhodopsin in rod cells
GPCR pathways Explain: 1. Adenylyl cyclase 2. PLC 3. Phosphodiesterase 4. PLA2
Explain!!!
- AC: Microtubule transport, secretion, changes in cell shape, lipid or glycogen breakdown, gene expression alteration, protein synthesis
Key factors: Ligand -> Adenylyl cyclase -> increase cAMP -> stimulate PKA (cAMP-dependent PK) -> cAMP-released PKA catalytic domain enter nucleus and (P) CREB -> (P) CREB binds to CRE -> transcription of cAMP-regulated genes - PLC -> Galpha activate PLC -> affect PPL in membrane producing: DAG and IP3
-> IP3 migrate to ER -> stimulate release of Ca2+
-> DAG will stay on PM -> activated by binding of Ca2+ from ER to form complex with PKC = activated PKC
Note: Ca2+ will also act as a 2nd messenger; will regulate troponin, calmodulin, and synaptotagmin - cGMP Phosphodiesterase
Photon/Light binds to GPCR -> GTP exchange -> Gbeta-gamma activates PDE -> decrease in cGMP -> low cGMP = closed cGMP-gated ion channel (Na+ and Ca2+ can’t enter)
*there’s signal amplification - PLA2 (*and PLC-beta leads to production of arachidonic acid from PPLs in PM)
Arachidonic acid pathways: - Cyclooxygenase (COX) pathway
COX -> PGG2 -> COX -> PGH
+ Thromboxane synthase -> thromboxane = platelet aggregation, vasoconstriction of small bvs
+ Prostacyclin synthase -> Prostacyclin = inhibit platelet agg, vasodilation
+ Cell-specific metabolism —> Prostaglandin (PGD2, PGE2, PGF2) = platelet aggregation, bronchoconstriction, renin release, inflammation - Epoxygenase (Cyt P450)
- > Other HETEs and EETs = release intracellular Ca2+ stores, cell proliferation - 5-Lipoxygenase
- > Produce leukotrienes = cause inflammation
NSAIDs (nonsteroidal anti-inflammatory drug)
-inhibits COX
True or False. 1 cell can have several receptors specific for different signaling molecules.
True.
Nitric oxide/cGMP signaling
A. Type of receptor (based on location)
B. Mechanism
A. Intracellular receptor: Guanylyl cyclase receptor
B. Mechanism:
ACh binds to GPCR -> PLC activated until production of NO (gas, prod by endothelium NO synthase act by Ca2+) -> NO will diffuse to smooth muscle cells binding to receptor -> converting GTP to cGMP and PPi -> cGMP stimulate PKG -> relaxation of muscle cell
What are molecular switches?
Interactions taking place within the cell that act to turn on or off proteins
What happens when you have V. cholera infection?
Enterotoxin secreted modifies Galphas = no GTPase activity so always on = severe watery diarrhea = dehydration and death
Enzyme-linked receptors
- Catalytic receptors
- Cytokine receptor
- CATALYTIC RECEPTOR
A. Receptor Guanylyl Cyclase
GTP -> cGMP (inc) leading to activation of PKG (cGMP-dependent protein kinase G) -> Phosphorylates target protein
E.g. ANP = increase in urine sodium
B. Receptor Ser/Thr Kinases
E.g. TGF-beta
2 subunits:
Ligand binds to subunit II -> Ser/thr in subunit I will be activated -> phosphorylation of receptor -> SMAD binds to activated receptor then gets phosphorylated -> SMAD dissociates and binds a different SMAD -> SMAD dimer translocates to nucleus -> gene transcription
C. Receptor Tyrosine Kinase (RTK)
2 classes:
i. Nerve growth factor
ii. Insulin (dimer ligand binds -> activation of receptor = autophosphorylation of receptor -> intracellular proteins bind to phosphorylated sites)
2 intracellular signaling proteins:
i. MAPK pathway
-> Intracellular signaling proteins will activate Ras protein (GTP binds) -> Ras will (P) Raf -> Raf (P) Mek -> Mek (P) Erk -> Changes in gene expression or protein activity
ii. IP3 kinase pathway
- > Activated PI3K -> PI3K will convert PIP2 to PIP3 -> recruit and (P) of PKB by PDK1 -> PKB phosphorylates BAD = inactive BAD; inactive death-inhibitory protein connected to BAD will now be active bc of phosphorylation = inhibition of apoptosis
- CYTOKINE RECEPTOR
Tyrosine Kinase-Associated Receptor (JAK-STAT)
-associated with proteins having tyrosine kinase activity
Cytokine binding -> Cross phosphorylation of JAK tyrosine kinases -> kinases phosphorylate the receptor -> STAT attaches to receptor and gets phosphorylated too -> STAT dissociates and dimerizes -> STAT migrates to nucleus -> Transcription
