Signaling via small molecules Flashcards
three mechanisms of small molecule signalling
- independent of plasma membrane proteins
- through ion channels
- downstream of G protein coupled receptors
what molecules can diffuse into a cell
small, hydrophobic molecules can diffuse into the cell
hydrophobic moles
diffuse completely
O2, CO2, N2, steroid hormones
small uncharged polar molecules
diffuse a little
H2O, urea, glycerol, NH3
large uncharged polar molecules
diffuse very little
glucose, sucrose, etc
ions
dont diffuse at all
H+, Na+, HCO3-
how do small hydrophobic signalling molecules diffuse into the cell
they are transported by carrier proteins to help them move them through hydrophilic extracellular space
They are released from the carrier and diffuse into target cell
They are often bound by nuclear receptor superfamily proteins within the cell
Nuclear receptor superfamily protein structure
N terminal transcriptional activating domain activates transcription of target genes
The middle DNA binding domain binds promoters of specific target genes
C terminal ligand binding domain binds to hydrophobic signalling molecules
orphan nuclear receptor
binds unknown ligands
how are the nuclear receptor superfamily proteins both receptors and effectors
Ligand binding causes a conformational change in the protein
DNA binding domain is now free to bind promoters of target genes
Inhibitory proteins are released and coactivator proteins are recruited
Nitric oxide
it can rapidly diffuse to signal to nearby cells
its made from arginine
it is fast and locally acting due to instability
it can diffuse out of endothelial cell and activate signaling in smooth muscle cell
what is both the effector and recdeptor for NO
guanylyl cyclase
ion channel coupled receptors
they are gated by a signaling molecule, they are usually closed until a signal is received.
Once open, channels mediate passive transport: ions will flow down their electrochemical gradient
resting synapse
- synaptic vesicles of neurotransmitters are waiting near the plasma membrane of the pre-synaptic cell
- gated ion channels in the target cell are closed
Active chemical synapse
- A nerve impulse causes neurotransmitter release by vesicle fusion to the plasma membrane
- Neurotrasmitters I the extracellular space open the ligand gated ion channels in the target cell
- Ions move into the target cell down their concentration gradient, triggering responses in the target cell
GPCRs
7 transmembrane domain proteins
subunits in GPCRs
G alpha, G beta and G gamme
how does an activated GPCR work
it acts as a GEF to exchange GDP for GTP on the G alpha subunit
GTP bound G alpha is active
Once activated, GTP G alpha dissociates from G beta gamma}Both G alpha and G beta gamma can activate different targets
what does regulator for G protein signalling (RGS) act as
it acts as a GAP to promote GTP hydrolysis by G alpha
what happens to G apha over time
over time GTPase activity of G alpha hydrolyzes GTP to GDP
GDP bound G alpha will re-associate with G game beta
how can different G proteins signal
- some signal through adenlyl cyclase to make cAMP
- some activate phospholipase enzymes to signal through lipids and Ca2+ channels
cAMP
small molecule secondary messenger
cellular concentration of cAMP are usually very low but large amounts are made in response to signals
what is cAMP synthesized from and broken into
it is synthesized from ATP by adenlyl cylase and it is broken down to AMP by cAMP phosphodiesterase
hw does G alpha activate adenlyl cylase
GPCR activates the heterotrimeric
G-protein complex Gs
GTP-bound G⍺ from Gs activates
adenylyl cyclase
adenylyl cyclase converts ATP to
cAMP
inactive PKA
4 subunits: 2 regulatory subunits, 2 catalytic subunits
active PKA
2 molecules of cAMP bind each regulatory subunit
Catalytic subunits are released and are now active kinases
Gs signaling via cAMP, PKA and CREB
- Ligand binds and activates the GPCR
- Activated GPCR acts as a GEF to exchange GDP for GTP on the G⍺ subunit of Gs
- GTP-G⍺ activates adenylyl cyclase
- Adenylyl cyclase coverts ATP to cAMP
- cAMP binds regulatory subunits of PKA to release the catalytic domains from inhibition
- Activated PKA moves to the nucleus
- Activated PKA phosphorylates CREB
- CREB-binding protein + phosphorylated CREB bind the cAMP-responsive element (CRE) to activate the transcription of target genes
what does each olfactory neuron express
many copies of only one GPCR type per neuron in the cilia
how do olfactory GPCRs signal through Golf and cAP
- Odorant recognition activates
the GPCR, which activates Golf - Golf triggers cAMP production
- cAMP opens cAMP-gated
cation channels - Cation influx triggers an action
potential
how do some G proteins signal by triggering phospholipase C - beta
GPCR activates the heterotrimeric G-protein complex Gq
* GTP-bound G⍺ from Gq activates phospholipase C-β
how do some G proteins signal by triggering diacylglycerol and IP3 production
Phospholipase C-β (PLCβ) cleaves PI(4,5)P2 to produce diacylglycerol (DAG) & IP3
* DAG diffuses in the membrane to activate protein kinase C (PKC)
* IP3 diffuses in the cytoplasm to open Ca2+ channels in the ER
* Both DAG & IP3 are small molecule secondary messengers
Gq signaling via DAG< IP3, Ca2+ and PKC
- Signal activates GPCR
- GPCR makes GTP-G⍺ on Gq, releasing Gβ𝛾
- GTP-G⍺ & Gβ𝛾 activate PLCβ
- PLC cleaves PI(4,5)P2 to DAG & IP3
- IP3 opens a gated Ca2+ channel
in the ER - Ca2+ moves into the cytoplasm
- DAG & Ca2+ activate PKC
- PKC phosphorylates downstream
targets
