Signal Transduction Flashcards by Amin Bemanian

Steps involved in signal transduction

Traverse the plasma memebrane
Transduced through cytoplasm to nucleus
Change gene expression

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Definition of Paracrine Signaling

Local mediators secreted by signaling cell to surrounding target cells

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Definition of Autocrine Signaling

Mediators are secreted and received by same cell

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Definition of Synaptic Signaling

NT release from neuron to a post-synaptic target (neuron or myocyte)

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Definition of Endocrine Signaling

Hormone release into blood stream to carry them to distant target

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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

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Definition of Intracellular Steroid Signaling

Lipophilic signaling molecules that interact in cytoplasm or nucleus, receptors are ligand-activated TFs

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Components of steroid receptor

Hormone-binding site
DNA-bindgin domain
Transcription-activating domain

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Action of steroid receptor upon binding to steroid

Dissociation from inhibitory proteins so DNA-domains can bind

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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)

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Therapeutic importance of glucocotricoids

Agents for anti-inflammatory regulation

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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

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5-Subunit Ionotropic Receptors

ACh, GABA, Serotonin, Glycine

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4-Subunit Ionotropic Receptors

Glutamate

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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)

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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