Lecture 10 Flashcards
What do hydrophillic hormones bind to?
plasma membrane through receptors and activate signal transduction pathways
What do hydrophillic hormones activate?
signal transduction pathways
What do receptors activate?
*some receptors activate G switch proteins that trigger a variety of signal pathways or induce the generation of intracellular second messengers
*other receptos are tyrosine kinases that trigger signal transduction pathways involving sequential activation of downstream kinases
What do hydrophobic hormones do?
diffuse through the cell membrane and activate cytosolic receptors which initiates signal transduction pathways
What are the steps to the action of hydrophillic hormones activating a receptor?
*Step 1: In this generalized pathway, receptor protein R binds ligand H.
Step 2: triggers a conformational change in the receptor (R) that enables it to bind to and activate a signal transduction protein S1
*Often a GTP-binding protein or a protein kinase or phosphatase
*Step 3: S1 in turn binds to and activates (or inhibits) other signal transduction proteins (S2)
*Step 4: S2 in turn activates other signaling proteins (here S3, S4, and S5)
*signaling proteins can activate multiple types of different downstream proteins
*Step 5: certain signal transduction proteins bind and activate an effector protein, E.
*can be an enzyme, transcription factor, transport protein, ion channel, or other type of protein
*Step 6: most signal transduction pathways have feedback controls whereby a protein in the signal transduction pathway (here S5) or an effector protein modifies either the receptor or an early protein in the pathway
What are the three types of extracellular molecule signalling?
*Extracellular molecule signaling – three classifications; based on distance over which the signal acts:
*(a) Endocrine
*(b) Paracrine
*(c) Autocrine
*(d) Membrane protein signals: signal neighboring cells by direct contact with surface receptors
What is endocrine signalling?
occurs by - epinephrine insulin
*Signaling molecules – synthesized and secreted by signaling cells (e.g., cells in endocrine glands)
*Transported through the circulatory system
*Affect distant target cells expressing the receptor
What is paracrine signalling?
occurs by - neurotransmitters, growth factors
*Signaling molecules secreted by a cell – affect only nearby target cells expressing the receptor
*Some may bind to ECM – released only when ECM is degraded
*close proximity cells
What is autocrine signalling?
occurs by - growth factors
*Cells respond to signals they secrete. (Tumor cells may overproduce and respond to growth factors.)
What do receptors do?
function as TF or activate G protein switches that regulate a variety of downstream pathways or induce the generation of intracellular second messengers that do so
What do kinases and phosphatases do in signal transduction?
protein phosphorylation by kinases and dephosphorylation by phosphatases regulate protein activity in the cellular pathways and can amplify intracellular signalling
What is an overview of both hydrophillic and hydrophobic cell signalling?
*Extracellular signaling molecules – synthesized, packaged into secretory vesicles, and secreted by specialized signaling cells within multicellular organisms
*Signal – produces a specific response only in target cells expressing receptor proteins that bind the signal
*Hydrophobic signaling molecules – (steroids and related molecules)
*Step 1: Diffuse through the plasma membrane
*Step 2: Bind to cytosolic receptors
*Step 3: Receptor-signal complex moves into the nucleus – binds transcription-control regions in DNA to activate or repress gene expression
*Hydrophilic signaling molecules – (small molecules [adrenaline, acetylcholine], peptides [yeast mating factors, glucagon], and proteins [insulin, growth hormone])
*Cannot diffuse across the cell membrane
*Step 4: Bind to specific cell-surface receptor proteins – triggers receptor conformational change that activates the receptor
*Step 5: Activated receptor activates one or more downstream signal transduction proteins or small-molecule second messengers.
*Step 6: Signal transduction proteins or small-molecule second messengers activate one or more effector proteins.
*Step 7a: Effector – stimulates modification of specific cytosolic proteins; short-term (sec-min) changes in cellular function, metabolism, or movement
*Step 7b: Effector – moves into the nucleus; triggers long-term (hours-permanent) changes in gene expression
*Termination or down-modulation of the cellular response –
*Step 8: Negative feedback/feedback represssion from intracellular signaling molecules
*Step 9: Destruction of the extracellular signal
What are the steps to hydrophobic signalling molecule?
- hydrophobic hormones diffuse through the cell membrane
- in the cytoplasm they bind a receptor/activator
- very often the receptor is a txl activator residing in the cytoplasm
- the receptor-hormone complex is recognized by a transporter molecular that takes it to the nucleus
What are the steps to hydrophillic signalling?
- the binding of the signal molecule (hormone) to a specific cell surface receptor leads to a conformational change in the receptor and its activation
- activated receptor initiates downstream signal transduction proteins and/or second messengers
- signal transduction leads to the activation of effector protein(s) causing
a) short-term responses OR - cytoplasm
b) long-term responses - nucleus - termination (or down-regulation) from negative feedback OR
- removal of the extracellular signal from the receptor
What is a special characteristic of membrane receptors?
they bind only a single type of hydrophillic signalling molecule, they are highly specific to their ligands
What are some examples of hydrophilic signalling molecules?
- small molecule: adrenaline, acetylcholine
- peptides: glucagon
What do secondary messengers do?
carry and amplify the signals from activated receptors/hormone complexes to effector molecules
All secondary messengers are:
- small short-lived molecules
- diffuse rapidly
- allow enzymatic amplification
What are the water soluble and lipid soluble secondary messengers?
Water soluble:
Ca2+ ions, cAMP, cGMP
Lipid soluble:
DAG, IP3
What can kinase/phosphatase activity be regulated by?
phosphorylation - can activate or inhibit protein function
binding to other proteins
binding of second messenger small molecules
specific protein phosphatases oppose the effects of kinases by removing the phosphate
Explain the cycle of protein activation by phosphorylation?
An inactive target protein is phosphorylated by protein kinase using ATP (ATP->ADP)
This causes the target protein to become active, it then transmits the signal
The target protein is dephosphorylated by protein phosphatase which causes the protein to become inactive
What are the two types of kinases in animal cells?
- tyrosine kinases
- serine/threonine kinases
How many kinases and phosphatases does the human genome encode?
> 600 different protein kinases (1.7% of all genes)
200 different protein phosphatases
What are G-protein coupled receptors?
GPCR
hydrophillic hormones bidn to membrane receptors called GPCR’s which activate G-proteins (GTPase switch proteins)
What do G-proteins do?
*once they are activated by GPCR’s, they exchange GDP to GTP leading to a conformational change and activation of the receptor
What is a special characteristic of G-switch proteins?
they have intrinsic GTPase activity which can be accelerated by GTPase-accelerating proteins
What do GTPase accelerating proteins do?
GAPs
accelerate GTPase activity in G-switch proteins
GAP
GTPase accelerating protein
What occurs in the G-protein once it send the signal to make a conformational change?
inactivates itself by hydrolyzing GTP to GDP
Explain the cycle of activating a G-switch protein to send a signal?
An inactive G-protein (has GDP bound) is activated by an activator protein called GEF (guanine nucleotide exchange factor) - this turns GDP into GTP
This causes the G-switch to become active (has GTP bound) - this is where it transmits a signal
The active G-switch protein them becomes inactive when an inactivator protein called GAP (GTPase-activating protein) and RGS (regulator of G protein signalling) intactivates the G protein causing a phosphorylation of GTP to GDP
What activates GAP protein?
a downstream molecule activates a gap protein
Where does the G-switch protein send its signal?
downstream
What causes the conformation change by the G-switch signal
altered by GTP/GDP binding
What can inactive and active G proteins interact with?
Inactive (GDP bound) G protein is capable of interacting with upstream activators
Active (GTP bound) G protein is capable of interacting with downstream effector proteins
What does the downstream effector protein produce?
secondary messenger molecules
how is cAMP synthesized from andenylyl cyclase and phosphodiesterase>
*>30 different mammalian GPCRs activate Gαs activation of adenylyl cyclase production of cAMP as a second messenger. (Most cell types express one or more such GPCRs.)
*Adenylyl cyclase (AC) – catalyzes formation of cyclic cAMP (second messenger) bond from ATP precursor
*cAMP phosphodiesterase (PDE) – catalyzes hydrolysis of cyclic bond – AMP (not second messenger)
*Similar reactions occur for production and destruction of cGMP second messenger.
what is cAMP?
second messenger
What are the steps of amplification of epinephrine receptor?
*single epinephrine molecule binding to one G protein coupled receptor activates up to hundreds of G proteins
*each G protein activates 1 adenylyl cyclase until G protein hydrolyzes GTP
*adenylyl cyclase catalyzes the synthesis of a large number of cAMP molecules while activated
*two cAMPs activate two protein kinase A (PKAs)
*activated enzyme can be produced through amplification and then more amplification to produce the product
