Signal Transduction Flashcards
Steps involved in signal transduction
Traverse the plasma memebrane
Transduced through cytoplasm to nucleus
Change gene expression
Definition of Paracrine Signaling
Local mediators secreted by signaling cell to surrounding target cells
Definition of Autocrine Signaling
Mediators are secreted and received by same cell
Definition of Synaptic Signaling
NT release from neuron to a post-synaptic target (neuron or myocyte)
Definition of Endocrine Signaling
Hormone release into blood stream to carry them to distant target
Definition of plasma membrane-bound receptor
Signaling molecule is a TM protein whose extracellular domain is a ligand for receptor on target cell
Direct contact between cells
Definition of Intracellular Steroid Signaling
Lipophilic signaling molecules that interact in cytoplasm or nucleus, receptors are ligand-activated TFs
Components of steroid receptor
Hormone-binding site
DNA-bindgin domain
Transcription-activating domain
Action of steroid receptor upon binding to steroid
Dissociation from inhibitory proteins so DNA-domains can bind
Glucocorticoid Receptor Mechanism
Cortisol carried by corticosteroid-binding globulin (CBG)
Cortisol activates glucocorticoid receptor (GR) in cytoplasm
GR dissociates from IP and HSP70 to enter nucleus and activate effector site (GRE)
Therapeutic importance of glucocotricoids
Agents for anti-inflammatory regulation
Types of membrane receptors
Ion Channel-Linked - Ligand regulates channel permeability
GPCR - Nuff said
Enzyme-Linked Receptor - Ligand activates enzymatic activity on receptor’s catalytic domain
5-Subunit Ionotropic Receptors
ACh, GABA, Serotonin, Glycine
4-Subunit Ionotropic Receptors
Glutamate
Structure and Mechanism of Nicotinic AChR
5 Subunits - Alpha 1/2, Beta, Gamma, Delta
ACh binds to alpha subunits to open the channel
Cation influx causes depolarization (excitatory)
Location of Nicotinic AChR
Neuromuscular Junction (NMJ)
PNS
CNS
GABA Mechanism
GABA binds to receptor
Cl channel opens
Influx of Cl
Hyperpolarization and inhibitory response
Barbituate and benzodiazepine effect on GABA receptors
Cause GABA receptors to be hypersensitive to GABA
Signalers of GPCRs
Neurotransmitters Light Odorants Hormones Growth Factors Cytokines
What links GPCR to effector enzymes?
Heterotrimeric G proteins
Subunits of G proteins
G-alpha: Binds to GTP, interacts with effectors, GTPase activity
G-beta/gamma: Inhibits alpha, anchors to membrane, has its own effectors
Types of G-alpha subunits
Gαs - Stimulates adenylyl cyclase
Gαi - Inhibits andeylyl cyclase
Gαq - Activates PLC
Tyrosine Kinase Receptor - Structure
Single protein with one TM which dimerizes upon binding of ligand or two subunits which tetramizes upon binding of ligand
Usually have a tyrosine kinase domain in cytosol but can bind with separate tyrosine kinase
Effects of ligand binding on Tyrosine Kinase Receptor
Dimerization
Cross-autophosphorylation
Binding of intracellular signaling molecules
Clinical consideration of Tyrosine Kinase-Linked Receptors
Cell proliferation and differentiation
Hormones, such as insulin
Growth Factors: EGF, PDGF, VEGF
Example of Serine/threorine-specific protein kinases
PKA, PKC
Ca/calmodulin-dependent kinase (CaM Kinase)
MAP Kinases (ERK, JNK, or p38 kinase)
Definition of dual specificity kinases
Phosphorylates both threonine and tyrosine
Example: Certain MAP Kinases
cAMP Generation
Gαs - Activates adenylyl cyclase, activated adenylyl cyclase converts ATP to cAMP
cAMP Effector
PKA
DAG/IP3 Generation
Gαq activates Phospholipase C to cleave PIP2
DAG/IP3 Effector
DAG activates PKC
IP3 releases calcium from the ER
Calcium generation
Generation: Generated by opening of ion channels
Calcium effectors
Effectors: Binds to proteins and activates PKC and other kinases and enzymes
Examples of Monomeric G Proteins
Ras, Rho, Rac, Rap, Rab
AKA: Small GTPases, p21 proteins
Regulation of monomeric G proteins
Activation by GEFs (Guanine Nucleotide Exchange Factors)
Deactivation by GAPs (GTPases Activating Proteins)
Ras-MAP Pathway
TRK + Adapter + GEF -> Ras (Activated monomeric G protein) -> Raf (MAPKKK) -> MKK1 (MAPKK) -> ERK (MAPK) -> MAP (Transcription Factor)
GEF: SOS
Adapter: GRB2
Clinical significance of EGF Receptor
Mutations cause cell proliferation
Gefitinib and erlotinib are tyrosine kinase inhibitors, tumor supressors (80% efficacy in mut. EGFR patients/10% efficacy in normal EGFR patients)
EGFR mutations more common in female Asian non-smoker adenocarcinoma patients
Definition of attenuation of signal
Turning off signaling molecules
Accomplishing attenuation of signal
Ligand inactivation or dissociation from the receptor
Receptors dissociate
Adaptor protein complexes dissociate
GTPase activity of G proteins
Kinase vs phophatases
Second messengers are metabolized or diffuse away
Ions are sequestered or pumped out
