Module 7 - Cell response to the environment Flashcards
Types of signalling
1) Cell-to-cell contact
2) Ligand diffusion:
Either local (adjacent cells through interstitial space) or distant
Cell-to-cell contact
Plasma membrane-bound signal molecules are used to directly signal with adjacent cells (called locally-paracrine signalling when this happens within one tissue, called locally-neuronal when signalling is neurotransmission between neurons)
Long distance contact
Hydrophobic signals that can pass the plasma membrane and bind to receptors in the cell (called remote-endocrine signalling when this process involves transport through the blood)
Types of signal transmission
1 signal - 1 receptor
1 signal - 2 receptors (two effects, ie ACh - nACh receptor in skeletal muscle and mACh in heart muscles (in response to increased effort demands))
1 signal - 1 receptor but in different cell types (ie ACh - mACh in heart muscles (slower) and mACh in salivary glands (in response to food))
Cell-surface receptors
Ion-channel coupled (open/close)
G-protein coupled (G-protein (de)activated)
Enzyme coupled ((de)activate associated enzyme)
How are cell responses to signals regulated?
Although one signal may bind to many receptors, the cell often has molecular pathways that control the effect of the interacting signal
These pathways are mostly different in different cell types so it allows for regulation
G protein signal transduction
As the ligand binds to the GPCR and the G protein is activated, it activates the effector in the intracellular side
Inactive G proteins
When GTPase converts its GTP into GDP, the G protein becomes inactive
An inactive G protein is a trimeric complex located in the plasma membrane composed of an α, β, and γ unit
Active G proteins
When GDP dissociates and GTP binds, the G protein becomes active
An active G protein dissociated into an active α unit and an active βγ complex
What do G proteins actually do?
Causes an immediate change in cell behaviour - ie opening/closing ion channels, activating secondary messengers
Secondary messengers: what are they and what are some examples?
Quickly produced, diffusible signalling molecules that activate effector proteins that can easily be inactivated again
cAMP, DAG, and IP₃
Signal amplification in signal transduction
Primary transduction, relaying the information to the secondary messenger, amplification, divergence to multiple targets
This allows strong activation in a short amount of time
Signal termination in signal transduction
Negative feedback causes the receptor protein to be recycled and the bound signal molecule to be degraded
cAMP: how does its conversion work, and what makes it a good secondary messenger?
Adrenaline binds to the GPCR, activating it and causing it to activate adenylyl cyclase which concerts ATP into cAMP (which activates PKA)
It can be quickly formed and inactivated by phosphodiesterase
PKA activation, structure, and function
PKA has cAMP binding sites on each polypeptide chain which allows for it to be activated
PKA is a serine-threonine protein kinase with two catalytic subunits with each one attached to one polypeptide chain with both chains being bonded by disulfide bridges
PKA, once activated, moves to the nucleus where it affects the transcription of certain genes by phosphorylation transcription factors
DAG and IP₃ activation, structure and function
GPCR activated - phospholipase C active - cleaves PIP₂ into IP₃ and DAG
Phospholipases C
Three main groups:
PLCβ - activated by GPCRs (cleaves into DAG and IP₂₃)
PLCγ - activated by RTKs (cleaves into DAG and IP₂)
PLCδ - in the cytoplasm (cleaves into DAG and IP)
DAG structure
1,2-diacylglycerol (DAG) - glycerol with fatty acid tails at the first and second carbons
IP₃ structure
IP₃ - Inositol 1,4,5-trisphosphate – glucose molecule but with the O-H bonds replaced with O-PO₃²⁻
PKC: what is it, how is it activated, and what does it do?
A serine-threonine protein kinase that is recruited to the membrane from the cytosol and binds with its C2 region to DAG
IP₃ binds to the endoplasmic reticulum and causes calcium ions to be released into the cytosol where it binds with PKC in its C1 region and activates it
Once activated, PKC phosphorylates substrates using its C4 region to bind and the C3 region which contains ATP
PKC structure
Regulatory domain:
N-C2 (binds to DAG)-PS (pseudosubstrate site)-C1 (calcium ion binding site)-catalytic domain
Catalytic domain:
Caspase cleaving site-C3 (ATP)-C4 (substrate binding site)-C
Different types of PKC: what is the difference?
Some PKCs do not require calcium ions for activation (no C1 present)
Phosphorylation: what does it do, what amino acids are targeted, and what is the major part of it?
Acts as a molecular switch
Amino acids with hydroxyl groups (serine (Ser/S), tyrosine (tyr/Y), and threonine (Thr/T))
The reaction is reversible as protein kinases phosphorylate and protein phosphatases dephosphorylate
Phosphorylation cascades: what is involved and what is an example?
Often involve multiple protein kinases
mitogen-activated protein kinases (MAPK) cascade
RTKs: what are they, why are they used, what do they do, and how does inactivation occur?
Receptor tyrosine kinases
Used to continue a signal that cannot pass through the cell membrane
The intracellular domain is used as an enzyme after dimerisation occurs and the RTK becomes active and it trans-phosphorylates (phosphorylates its own tyrosines on opposite sides) which act as binding sites for further signalling
The receptor moves by endocytosis into lysosomes for breakdown and the phosphates are removed by tyrosine phosphatases
RAS: what does it do and what types of RAS are there?
Acts as a molecular switch downstream from RTKs
- RAS - acting as a molecular switch in signalling
- RAS-GEF (guanine nucleotide exchange factor) - bound to ATP and swaps it with an ADP bound to the RAS, activating it
- RAS-GAP (GTPase activating factor) - removes the ATP bound to Ras, inactivating it
Adaptor proteins between RTKs and RAS-GEFs: what are the important binding points and what do they do?
SH2 binds to phospho-tyrosine residues (Y-P) in the RTKs
SH3 domain interacts with proline-rich sequences (found in the RAS-GEFs)
MAPK cascade: what is it and what does it do?
Mitogen-activated protein kinases (MAPK) cascade
Variety of functions:
* Enzyme phosphorylation - metabolism control
* Cytoskeleton phosphorylation - cell shape control
* Gene regulatory protein phosphorylation - gene expression control
Phosphatidylinositol kinases: what are they and what do they do?
Heterodimeric lipid kinases which phosphorylate as kinases
