lec 12- cell signaling and signal transduction Flashcards
what are the 8 steps to cell signalling?
- synthesis of the signalling molecule
- release of the signalling molecule via exocytosis
- transit of the signalling molecule to the target cell
- binding of signalling molecule (ligand) to a protein receptor
- binding of a ligand to a receptor results in conformational change of the receptor
- receptor initiates one or more intracellular pathways that results in changes in: cellular function, metabolism, gene expression, shape, movement
- deactivation of receptor
- removal of ligand
what are the 4 types of signalling systems?
autocrine, paracrine, endocrine, and juxtacrine
what does an autocrine signalling?
the messenger acts on receptors on the same cell
what is paracrine signalling?
the messenger molecule travels a small distance and works on cells adjacent from the one secreting them
what is endocrine signalling?
the messenger molecule travel through blood stream to other cells
what is juxtacrine signalling?
short range of signalling, but requires physical contact between cells
what are the three types of cell surface receptors?
-G-protein coupled receptors
-enzyme-linked
-ion channel linked
what are intracellular receptors?
receptors inside the cell that recieve signalling molecules that can pass through the membrane
what is the first messenger?
the ligand (messenger molecule)
what is the second messenger?
small molecules that increase or decrease in concentration in response to first messenger
what do second messengers bond to?
target proteins which undergo a change in activity
what does phosphorylation do?
changes a proteins charge and generally leads to a conformational change which alters ligand binding or other features of the protein resulting in an increase or decrease of its activity, phosphorylation is apart of almost all signalling pathways
what does kinase and phosphotase do?
kinase phoysphorylates meaning it adds a phosphate group, phosphotase dephosphorylates meaning it removes a phosphate group
what 3 amino acids get phosphorylated the most?
serine,threonine, tyrosine
what helps GTPase turn GTP into GDP, and what helps GTPase turn GDP into GTP?
GTP to GDP- GAPs, RGSs, GDIs
GDP to GTP- GEFs
what is signal amplification?
a small amount of ligand can initiate a large response from a target cell, a large release of second messengers (ripple effect)
what are the three ways in which signalling can be integrated?
- one receptor activates multiple pathways
- different receptors activate the same pathways
- different receptors activate different pathways which affect one another
why do signalling proteins have domains?
so they can interact with other molecules simultaneously
what does SH2 domain do?
binds to phosphorylated tyrosine so proteins can interact with one another
can signals combine in different ways to generate different outcomes?
yes
what are the four types of messengers and their receptors?
- ligand-gated ion channels
- G protein-coupled receptors
- receptor kinase
- Nuclear receptor
what do ligand-gated ion channels do?
ligand-gated ion channels- conduct flow of ions across the plasma membrane to change its potential
what do G protein-coupled receptors do?
G protein-coupled receptor- contain seven transmembrane a-helices and activate GTP-binding proteins
what does receptor kinase do?
receptor kinase- dimerize and activate their cytoplasmic protein kinase domain to phosphorylate specific tyrosine residues of cytoplasmic substrate proteins
what do nuclear receptors do?
function as ligand-regulated transcription factors
how many subunits does the G-protein have?
3 which are alpha (a), beta (B), and gamma (Y)
what is the alpha subunit of a G protein?
a GTPase
how many G protein coupled receptors are in humans?
700
are G protein coupled receptors found in all eukaryotes?
yes
what are the types of signalling molecules (ligands)?
proteins, peptides, amino acid derivatives, fatty acids, photons, olfactory molecules
what part of the G protein coupled receptor is outside, in the middle, and inside?
amino terminus is outside, seven a-helices in the middle of the plasma membrane, and a carboxyl terminus inside
what is the general structure of a G protein coupled receptor?
7 transmembrane a-helices, ligand binding site, cytosolic portion that interacts with large G proteins, GRK phosphorylation sites for receptor downregulation, PKA is activated by GPCR and also can participate in downregulation
what does ligand binding to the G protein coupled receptor cause?
binding to the receptor extracellular domain causes a conformational change of its intracellular domain, receptors affinity for G proteins increase and the receptor binds the trimeric G protein, A GDP is exchanged for GTP on the Ga subunit which activates it and promotes association with the effector
can one ligand bound receptor activate multiple G proteins?
yes
how is termination of G protein coupled receptor response done?
through multiple processes, one is Desensitization
what is Desensitization?
by blocking active receptors from turning on additional G proteins (even though ligand is still bound), proteins called arrestins compete with G proteins to bind GPCRs
what are the steps to signal transduction of G proteins?
- ligand binding induces conformational change in receptor
- receptor binds to G protein
- activated receptor results in conformational change in Ga triggering dissociation of GDP
- binding of GTP to Ga triggers dissociation of Ga both from receptor and GBy
- Ga binds to an effector causing it to activate
- hydrolysis of GTP to GDP in Ga results in dissociation with effector and reassociation with GBy
what are the types of effector proteins?
membrane ion channels, enzymes that catalyze the formation of second messengers
what do G proteins do to adenylyl cylase?
activate it resulting in it removing two phosphates as pyrophosphate, reaction is driven in forward direction by the hydrolysis of pyrophosphate
what is the life expectancy of cAMP?
short lived, unstable, hydrolyzed to 5’-AMP
what are first messengers and second messengers?
first = ligand
second = small molecules that increase or decrease in concentration in response to first messenger
what do second messengers bind to?
other proteins to modify their activity
what does cAMP activate?
protein kinase A
what are the main target proteins that protein kinase A phosphorylates?
serine and threonine
how many substrates does protein kinase phosphorylate?
over 100
how does PKA mediate so many types of signals?
by confinement of the signalling process to one part of the cell via adaptor proteins (AKAP)
what does AKAP confine PKA to?
actin filament, microtubules, ion channels, mitochondria, nucleus
what does AKAP5 function as?
a scaffold protein, confines PKA signal
how many types of AKAPs are there?
50
what do AKAPs do?
provide structural framework or scaffold for coordinating protein
what is substrate selection?
the closer substrates are selected first and phosphorylated by PKA attached to AKAPs
what causes several disorders in receptors or G proteins?
defects in the receptor, loss of function mutations resulting in nonfunctional signal pathways
what causes Retinitis Pigmentosa?
a progressive degeneration of the retina caused by the mutation in rhodopsins ability to activate G proteins
