Signal. Transduction Flashcards
What are the main purposes of cell- cell signaling and communication?
Key role in cellular processes such as proliferation, growth, differentiation, cellular mechanism and results in a variety of cellular responses
Regulation of:
- Gene 3xpression
- Metabolism
- Cell shape and cellular mechanism
- Neuronal signaling
Mis-regulating if signal transduction pathways:
- Cellular transformation (carcinogenesis)
- Endocrine disorders like diabetes mellitus, thyroid disorders
Summarize metabolism Regulation
Metabolic pathways coordinated to produce of energy or synthesize products to meet needs of cell and organism
Efficient communication system necessary to coordinate various functions
Regulation depends on:
- Intercellular signals
- Intracellular signals
Outline chemical(intercellular signals)
- Secretion stimulus
- Diffusion/receptor binding
- Diffusion into the cell
Compare intracellular vs cell-surface (plasma membrane) receptors
- Plasma membrane receptors have extracellular binding domains for ligand binding
- Intracellular receptors bind lipophilic/hydrophobic (steroid hormones or other messengers ) that diffuse through plasma membrane
-Intracellular receptors present in
-Cytoplasm and translocate to the nucleus on binding to hormone
OR
-Nucleus and hormone receptor complex binds tonDNA
Describe cell surface receptors
- Hormone is hydrophilic
- Extracellular domain for binding hormone/signal
- Intracellular domain fir signal transduction
- Many produce second messengers within cells
- Rapid response; slower response effect
- Examples: Peptide hormones-insulin, glucagon, epinephrine, Acetylcholine; GABA; Eicosanoids
Describe Intracellular receptors
- Lipophilic/hydrophobic signals diffuse through plasma membrane
- Located in nucleus or cytosol
- Conformational change on binding hormone
- H-R Complex enter nucleus
- Bind to specific regions of DNA
- Influence transcription and translation (gene expression)
- Function like transcription factors
- Response is slower
- Steroid hormones, thyroxine, retinoids acid (Vit. A) and vitamin D
How can intercellular signals be converted to intracellular signals?
These are converted to an intracellular signal in the adjacent cell
Many extracellular signals (hormones) exert their effects by producing intracellular second messengers
What are the intercellular signals?
Endocrine- hormones(insulin, glucagon, epinephrine, steroid hormones, peptide hormones)
Paracrine. Neurotransmitters, some growth factors, eicosanoids, nitric oxide(gas)
Some growth factors( eicosanoids) —> autocrine
What are neuronal and contact signaling?
Neuronal- from nerve to target cell is synapse
Contact -cell signaling across gap junctions
Describe specificity as a feature of intracellular signal transduction (receptor mediated)
A) specificity- signal molecule fits binding site on its complementary receptor; other signals don’t fit
Each hormone has specific receptors
A hormone may have more than one receptor line epinephrine and norepinephrine have slpha1, 2nand beta receptors (different tissues)
Acetyl choline has muscuranic and nicotinic receptors
Describe amplification as a a feature of intracellular signaling mechanism
When enzymes activate enzymes of affected molecules increases geometrically in an enzyme cascade
Describe the features of desensitization/adaptation
Receptor activation triggers a feedback. Circuit that. Shuts off the receptor or removes it from cell surface
Describe integration as a feature of intracellular signal transduction
When two signals have opposite effects on aa metabolic characteristic such as the concentration of a second messenger X, or the membrane potential Vm, the regulatory outcome results from the integrated input from both receptors
“Outcome” is additive
What are the 4 basic types of signal transduction pathways mediated by 4 different types of receptors?
- Intracellular receptor (steroid receptor)
- Gated-ion channel
- receptor enzyme (catalytic channel)
- Receptors that form intracellular second messengers
Summarize the 4 general types of signal transducers
- Steroid receptors- steroid binding to a nuclear receptor protein allows the receptor to regulate the expression of specific genes
- Gated ion channel-opens or closes in response to concentration of signal ligand (S) or membrane potential
- Receptor enzyme- ligand binding to extracellular domain stimulates enzyme activity in intracellular domain
- Serpentine receptor- external ligand binding to receptor (R) activates an intracellular GTP-Binding protein (G), which regulates an enzyme (Enz) that generates an intracellular second messenger,X—> GPCR
Explain steroid and thyroid receptor family (intracellular)
Lipophilic hormones cross cell membrane to bind specific intracellular receptors
Examples include: testosterone, estrogen, cortisol, aldisterone (steroid hormone)
- Vit. D and ergonomic acid (Vit a )
- thyroid hormone (thyroid receptors)
Hydrophobic/Lipophilic hormones induce (Up-regulate) or repress/down-regulate gene expression at level of transcription
How do steroid-thyroid receptor family operate?
- Bind intracellular receptors
- Change in expression of target genes
- Increased production of protein (induction) or repression
Explain the functioning of steroid receptor signal transduction
-Hormone diffuses inti cell (Lipophilic/hydrophobic)
- Binds specific receptor (cytosol or nucleus)
- forms hormone-receptor complex; conformational change in receptor
- H-R complex enters nucleus
- H-R complex binds specific regions of DNA (hormone response elements (HRE)
- H-R complex binds enhancer regions, activates promoter, increases transcription (INDUCTION of gene expression) and translation to form protein —> cellular response
- If H-R complex binds repressor regions —> decreased transcription (repression of gene expression)
Outline steroid receptor signal transduction
- Binding of hormone receptor complex to HRE regulates expression of adjacent genes
- Increase or decrease rates of mRNA synthesis (transcription)
- Cause INDUCTION or REPRESSION of gene expression
- Works through modulating gene expression
- Hormone-Receptor complex works like a transcription factor
- Comparatively slow: response may take hours to days to be effective
How long does steroid receptor signal transduction. Take?
Works through gene expression
Comparatively slow; response may take hours or days
Outline ligand gated ion channels
- Binding of neurotransmitter causes channel to open
- Results in influx of ions through ion channels
- Alters membrane potential —> promotes or inhibits. Nerve impulse transmission
Some examples:
Nicotinic ACh receptors in parasympathetic ganglia and neuromuscular junction (muscle)
Glutamate receptors (lonotropic) in CNS
GABA-A receptors in CNS
Glycine receptors in CNS
Outline gated ion channels
- parasympathetic ganglia (autonomic nervous system)
- neuromuscular junction(muscle)
Nicotinic Acetyl choline receptors
There is a conformational change on binding to Acetyl choline
How is acetylcholine terminated?
Enters synaptic cleft or neuromuscular junction-signal is given
Cleaved by acetylcholine esterase (an enzyme)
Acetate and choline May be recycled
What are the receptor enzyme(catalytic receptor) mechanisms ?
Transmembrane catalytic receptors have intrinsic enzymatic activity
Enzyme is tyrosine-specific protein kinase (adds P to tyrosine)
Insulin receptor
- Extracellular domain for binding insulin
- Intracellular domain with tyrosine kinase activity
Binding of ligand (insulin)—> ATP cleavage and autophosphorylation of tyrosine residues insulin receptor tyrosine kinase (IR) —> and then phosphorylation of specific tyrosine side chains in target proteins
Summarize extracellular and cytoplasm activities of receptor enzyme
Extracellular, insulin binds
Insulin receptor activated, in the cytoplasm, ATP is then used to phosphorylates the IR on the cytoplasmic side of the IR
Activation of tyrosine kinase domains of IR by insulin binding, followed by autophosphorylation
What are the intracellular insulin receptor effects ?
- Intracellular effectors:
- Insulin receptors substrates: IRS 1-4
- Enzyme effectors: activation of PI3-kinase
- Multiple signaling pathways
- Cellular responses:
- Increased glucose uptake
- Regulation of transcription
- Activation of enzymes and regulation of metabolism
- Covalent modification
- Upregulation (increased synthesis of enzymes)
How does insulin stimulate glucose transport (GLUT-4) in adipose or muscle cells?
- Insulin binds to its receptor
- GLUT 4 translocation from Golgi to plasma membrane
- Vesicle containing GLUT 4 binds and fuses to plasma membrane
- Glucose transport allowed in response to insulin
- Insulin dissociates from receptor; inactivation
- Vesicle containing GLUT 4 trans located back to Golgi
The insulin receptor is a …
Dimer with two different types of subunits . It spans the membrane
Describe the subunits of insulin receptors
The B-subunits are tyrosine kinases. When insulin binds the subunits phosphorylate themselves at tyrosine residues.
The subunits also phosphorylate other protein kinases at tyrosine residues. These kinases produce the cellular responses
What receptors that form second messengers?
-Receptors pass signal (message) from outside cell by produc8ng sound messenger inside the cell
Types of receptors
- G protein coupled receptors
- Guanylate cyclase (cGMP)
Rapid and immediate effects
- Phosphorylation of enzymes (activation or inactivation of key regulated enzymes)
- Changes in ion levels (calcium)
Slower effects on gene expression
Covalent modification of enzymes
Outline G-protein coupled receptors and intracellular second messengers
- Hormone (first messenger) changes concentration of some other molecule (second molecule) inside the cell
- Generally small, non- protein molecules
- produced intracellular LH when hormone binds to its receptor
- Initiate cascade of intracellular events (enzyme activation/inhibition, altered gene regulation ) resulting in specific cellular responses
Example:
- Adenylate cyclase system produces cAMP
- Calcium- phosphatidylinositol system produces IP3, DAG, Ca2++
Summarize GPCR’s( G-protein coupled receptors), heptahelical receptors and second mass angers
The extracellular domain contains the binding site for a ligand (a hormone or neurotransmitter)
Intracellular domain that interacts with G-proteins
Seven transmembrane helixes
Summarize the heptahelicalreceptors GPCR’s and second messengers.
- Hormone (or cytokine or neurotransmitter) is first messenger
- Binds plasma membrane heptahelical receptors
- Hormone- receptor complex activates G-protein that activates membrane-bound enzyme (effector enzyme)
- Activation of different GPCRs lead to generation of different intracellular second messengers such as cAMP or DAG/IP3
What are heterotrimeric G proteins?
- Binding of hormone to receptor activates G protein
- The Galpha-subunit dissociates; binds GTP (Ga-GTP) is active
- Ga-GTP activates enzymes to produce intracellular second messengers
- Ga subunit has intrinsic GTPase activity (intrinsic timer)-termination of signal
What are the types of Ga ?
Alpha 1 adrenergic receptor: Gaq
- activates Phospholipase C
- Increases IP3, DAG, Ca2+(second messengers)
Alpha 2 adrenergic receptors(inhibitory) Gai:
- Inhibits Adenylate cyclase
- Decreases cAMP levels
Beta-adrenergic receptors; glucagon (stimulatory) : Gas:
- Activates Adenylate cyclase
- Increases cAMP levels
