Week 3 Flashcards
List the three major classes of cell-surface receptor proteins
- Ion-channel-coupled receptors
- G-protein-coupled receptors
- Enzyme-coupled receptors
Ion-channel-coupled receptors
• transmitter-gated ion channels – synaptic signalling induced by neurotransmitters (such as serotonin, glutamate)
• the channels are opened and closed depending on the signalling molecule resulting in a change in ion permeability across the membrane
• Ionotropic (distinct from receptors that generate 2nd messenger)
• Acetylcholine acts on ionotropic receptor in postsynaptic cells
• AchR is cation channel = Na+, K+, Ca2+ = depolarisation
G-protein-coupled receptors
• indirectly regulate another membrane bound target protein (second messenger)
• involve trimeric GTP-binding proteins which interact with the receptor and the effector e.g. adenylate cyclase (cAMP)
Enzyme-coupled receptors
• the receptor, when activated upon ligand binding have intrinsic enzymatic activity
• can also interact with associated enzymes
Intracellular messengers: First Messenger
- extracellular molecules that bind to the receptor
Intracellular messengers: Second messengers
• intracellular molecules that relay the signal through the cell.
• receive the signal from the extracellular messenger via the receptor
• can be small molecules (e.g. GTP, cGMP, cAMP, Ca2+, IP3 etc.)
• can be water soluble and hence present in the cytoplasm or can be lipid soluble and diffuse along the plane of the membrane (e.g. diacylglycerol)
• can be proteins e.g. SHC, Grb2
• pass the signal through the cell
ultimately binding to and changing the effector protein
Intracellular messengers: Effector Protein
• responsible for modifying the cell behaviour
• gives the final response of the cell to the original signal
Functions of Intracellular Messengers
The relay events that occur inside the cell have the following functions:
1) Transform the signal into a molecular form that can be passed along the pathway and ultimately stimulate a response.
2) The signal must be relayed from the primary receiving site to the final response production site.
3) Sometimes the signal is amplified along the signalling cascade.
This strengthens the signal (a single extracellular molecule can have a much more pronounced effect on the cell).
4) The signal may have to be distributed so that it influences more than one process in parallel.
5) The relay may be modulated by other factors along the pathway – these factors may come from other primary signaling molecules.
GPCR structure
All GPCRs have a similar structure
- Polypeptide chain traverses membrane as 7-alpha helices
- Cytoplasmic portion bind to a G protein inside the cell
- Receptors that recognise small molecules, binds deep in membrane
- e.g. Adrenaline
- Receptors that bind proteins have large extracellular domain
Activation and Interaction between GPCR and G protein
- Activated GPCR activates G proteins – a subunit exchanges GDP for GTP
- Unstimulated state, both receptor and G protein inactive
- Binding extracellular signal molecule to receptor changes conformation. Alters conformation of G protein
- Alpha subunit exchange GDP to GTP
- Additional conformation change,alpha and beta-gamma complex dissociate
- Interact with target proteins
- G proteins can interact with ion channels
- G protein directly couples receptor activation to opening of K+ channels in membrane of heart pacemaker cells
- Acetylcholine to GPCR in heart cells
Many G proteins activate membrane bound enzymes that produce small messenger molecules - Two most frequent targets for G proteins are adenylyl cyclase, which produces small intracellular signalling molecule Cyclic AMP
- Phospholipase C, which generates inositol triphosphate and diacylglycerol.
- Inositol triphosphate in turn promotes accumulation of Ca2+, yet another signalling molecule
What is metabolism
The conversion of food into energy &/ or components required by cells, & thus the body, to function
There are 2 forms of metabolism: Catabolism (big to small) and anabolism (small to big)
Normal metabolism includes variations due to:
- periods of starvation
- exercise
- pregnancy & lactation
Abnormal metabolism results from:
- nutritional deficiency
- enzyme deficiency
- abnormal secretion of hormones (e.g. diabetes)
ATP
- One of the most important energy vehicles in human cells - ATP = adenosine triphosphate, contains two “high energy” phosphate group bonds
- When a phosphate group is cleaved from ATP, ADP (adenosine diphosphate) is formed, energy released can be used to drive reactions in the cell
- Reactions occur all the time in cells, providing ATP when foods are broken down, & breaking down ATP to ADP or AMP when energy is required by the cell
- Human cells produce ATP & continually break it down & reform it, as required
Cellular Work
A cell does three main kinds of work
- Mechanical – e.g., muscle contraction
- Transport – e.g., cytoskeleton moving things
- Chemical – e.g., forming covalent bonds
Energy coupling is a key feature of how cells manage their energy resources.
ATP powers cellular work by coupling energy-generating reactions to energy-requiring reactions.
Enzymes
- Most reactions in a cell involve Enzymes
- Most enzymes are globular proteins
- Enzymes bind specific ligand (substrate), alter its configuration so that it is more easily changed into the product, while the enzyme itself is unchanged.
- Binding involves noncovalent interactions in active site.
- Organisation of atoms in the active site is optimised for substrate binding & catalysis.
Metabolic reactions
- Conversion of substrate(s) (reactants) into product(s).
- Substrate → Product
- Even the simplest reactions need enzymes
- Enzymes do not change the equilibrium of a reaction. If a reaction can’t take place, an enzyme won’t make it happen, but they do speed up reaction rate
Equilibrium
- Some reactions essentially proceed in only one direction, e.g., burning hydrocarbons in air – highly exothermic.
- Many reactions proceed in both directions:
- A + B → X + Y (1)
- X + Y → A + B (2)
- Starting with just A & B, only rxn 1 will occur
- As X & Y accumulate, so rxn 2 will also occur.
- Will eventually have mix of A, B, X & Y, when same relative amounts of A & B as X & Y… equilibrium.
- A+B ⇔ X+Y
- Equilibrium does not mean that [A&B] = [X&Y]
Equilibrium & Metabolism
Reactions in a closed system (unable to exchange matter or energy with its environment) eventually reach equilibrium & then do no “work”. This is irrespective of the direction of equilibrium, as reactions in one direction or the other may be favoured.
Closed system reactions proceed to equilibrium
The forward & reverse reactions may proceed at the same rate.
In a cell, virtually never get reaction equilibrium as cells are “open systems” – with enzymes, substrates & products continually removed &/or added.
Cells have constant flow of materials, preventing metabolic pathways from reaching equilibrium.
If our cells reach equilibrium, they die.
In metabolic reactions in cells, enzymes catalyse each reaction. Some enzymes catalyse the reverse reaction as well (i.e., both directions, so are reversible), while some reactions are essentially irreversible.
Metabolic Pathways
Metabolic pathways = multistep open systems
Product of each reaction becomes substrate for next, so reactions don’t reach equilibrium, & system is in continual flux.
Several reactions linked form a metabolic pathway
Often, the product of one reaction can influence another reaction in the sequence
Enzyme activity controlled in numerous ways – like protein shape change by de/phosphorylation.
Enzyme Compartmentalisation
Cell compartments (organelles) have role in bringing order to metabolic pathways.
Some enzymes are integral membrane proteins.
Mitochondrial Structure
Sometimes, enzymes in multi-step pathways located in different parts of organelle, such as mitochondria.
