Midterm 3 Flashcards
What is the cell signaling pathway
linked set of biochemical reactions that are initiated by ligand-induced activation of a receptor protein and terminated by a measurable cellular response
Components of signaling pathways
●First messengers: extracellular ligands that bind to receptor proteins, cause conformational change
●Second messengers: intracellular signaling proteins
What is signal transduction?
●biochemical mechanism responsible for transmitting extracellular signals across plasma membrane and throughout the cell
●also involves second messengers and a variety of intracellular signaling proteins
●function together to transmit, amplify, and terminate signal
what do first messengers do?
●binds to receptor proteins, causing conformational change in receptor
Consequences of signal transduction
●changes information into chemical signal
●often ends with covalent or noncovalent modification of intracellular target proteins (phosphorylation and dephosphorylation)
●altered rate of protein expression (at transcriptional or translational level)
First messenger examples
●Insulin: first 1st messenger protein to be discovered, discovered as treatment for diabetes
●Hormones: biologically active compounds that are released into circulatory system and come into contact with hormone receptors in target cells (generally hydrophobic and nonpolar)
●Other soluble gases (NO: generate in cells via oxidative deamination of arginine, causes vasodilation and increased blood flow) (sildenafil -> viagra : know backstory)(Bugs use NO increase blood circulation)
●Neurotransmitters
How do hormones travel?
●Endocrine hormones: produced by secretory glands and are exported into the circulatory system. long distance
●Autocrine and Paracrine hormones: small peptides that function over short distances to activate receptors on nearby cells (paracrine hormones) or on same cell (autocrine hormones)
Endocrine Hormones
insulin, estrogen, testosterone
Paracrine Hormones
serotonin, histamine, growth factors
Autocrine Hormones
interleukins and growth factors
What are secondary messengers?
small intracellular molecules that amplify receptor-generated signal
Secondary Messengers examples
Cyclic GMP (cGMP), cAMP, Diacylglycerol (DAG), Inositol-1,4,5-triphosphate (IP3), Ca2+
Signal Amplification
process by which a signal that is initiated at the cell surface leads to multiple downstream events through the action of enzyme-mediated catalyzed reactions like phosphorylation
What are the receptor protein classes?
GPCRs, KLRs, tumor necrosis factor receptors, and nuclear receptors
GPCR
●G protein-coupled receptors
●involved in sensory perception (vision, taste, smell)
●Globular protein with 7 transmembrane regions (hydrophobic and helical in shape), known as 7-TM receptors
●Many are glycoproteins (help with cell recognition) that contain carbohydrate functional groups directly attached to the extracellular domain
GPCR signal transduction
●transmit extracellular signals to cytoplasm through direct interaction with membrane-bound protein complex called heterotrimeric G protein (has a G α , G β, and G γ subunit)
●Gα is a GTPase (active when GTP bound, inactive when GDP bound)
●When the trimeric G protein binds to activated GPCR, GDP -> GTP, activating the Gα subunit. Causes dissociation of alpha subunit
●Dissociation of heterotrimeric G protein complex is common to all GPCRs
●lipid membrane anchors (can move but stay on membrane)
●Several different α, β, and γ subunits- causes unique effects
Different G alpha subunit examples
●αt, αs, αq
Gαt subunit effects
αt activated by GTP -> cGMP phosphodiesterase (break down phosphodiester bonds) -> GMP
●regulates synaptic transmission in light-stimulated vision (just one example)
Gαs subunit effects
αs activated by GTP -> ATP turned into cAMP by Adenylate cyclase -> cAMP triggers PKA (phosphokinase A) -> activates numerous target proteins
Gαq subunit effects
αq activated by GTP -> PIP2 converted to DAG and IP3 by phospholipase C (cleave phospholipids in membrane) -> (IP3 -> Ca2+) and (DAG -> PKC) -> regulates many processes
GPCR Signaling in Metabolism
●multiple diff stimuli work together to accomplish common goal
● glucagon, glycogen, epinephrine
●makes sense because they (glucagon and epinephrine) signal for same phenotypic response (increase blood glucose levels)
PKA’s role in Epinephrine (β2 Bound) and Glucagon
●Gsα activation of adenylate cyclase, produce cAMP that will activate Protein Kinase A, ***Turns off glycogen synthesis, turn on glycogen degradation and glucose synthesis -> net glucose export
Epinephrine (α1 Bound)
●Gqα activation of PLC -> PIP2-> DAG and IP3 -> (DAG activation of PKC -> turn off glycogen synthesis) OR (IP3 mediated calcium release from ER -> turn on glycogen degradation) -> Net glucose export
Catecholamines
●1st messengers, include epinephrine
●derived from Tyr
●target α and β adrenergic receptors. Tissue distribution and physiological responses governed by these two receptors are diverse, controlling from metabolism in liver, skeletal muscle, and adipose cells, to relaxation and contraction of smooth muscles
Receptor Agonists
●Activate receptor signaling by mimicking the natural ligand
●some endogenous agonists: dopamine and norepinephrine
● recognize the two OH antennas
Catecholamines Gαs
●β-2 receptors mostly in airway smooth muscles, epinephrine binding to β-2 receptors causes changes in Gαs subunit
●GDP bound state: Gαs interacts with Gβy through switch II helix region
●GTP binding to Gαs induces conformational change in switch II helix region so it’s positioned to bind with adenylate cyclase (perfect binding site for adenylate cyclase)
●adenylate cyclase becomes active upon binding to Gαs
●Elevated cAMP levels activate PKA
●cAMP binds to regulatory subunit of inactive PKA to create active PKA monomers
●4 cAMP bind to inactive R2C2 complex and cause conformational change to activate PKA
Epinephrine stimulation of β-2 consequences
●cause dissociation of Gαs-> produce cAMP
●cAMP will activate PKA (functions to phosphorylate various enzymes contributing to relaxation of airway smooth muscles)
●cAMP reduces Ca2+ by inhibiting outflow (preventing muscle contraction)
●albuterol is agonist (treat asthma and COPD)
Receptor agonist and antagonist
●Agonist: activate receptor signaling by mimicking natural ligand
●Antagonist: bind to receptor with high affinity and block binding of physiological agonists without promoting structural changes needed for signal transduction
Termination of GPCR Signal
●desensitization of receptor after Gαβγ dissociation
●regulatory proteins called G protein-coupled receptor kinases (GRK) phosphorylate GPCR cytoplasmic domain on Ser and Thr residues
●phosphorylation by GRK provides docking site on GPCR for 2nd protein (β-arrestin), a protein that binds to receptor and prevents reassociating with Gαβγ complex
●β-arrestin binding “flags” the GPCR for endocytic translocation to cytoplasm where GPCR is dephosphorylated (not reversible until dephosphorylated)
●After GPCR dephosphorylation in endocytic vesicles, receptor is either degraded or returned to plasma membrane for another round of signaling