Topic 1: Cell Communication [2-5] Flashcards
Define the cell as the basic unit of physiology Describe how signals can cross membranes Explain the different types of cell: cell communication Explain the different ways by which signals can be released from cells Give examples of different types of receptors Describe different speed of responses from multiple receptors Give examples to illustrate how the same signal can have multiple outcomes depending on the receptor Demonstrate how cell signalling pathways have potential as drug targets
What is the cell-to-cell junction called that join adjacent cells and is used for small soluble signals?
Gap junctions
How do a) Hydrophobic (1 way) and b) Hydrophilic (4 ways) molecules cross membranes?
a) Free diffusion
b) - Pumps / transporter
- ion channel
- vesicle fusion / fission (exo/endocytosis)
- indirectly, receptors & signalling pathways
Name some examples of signalling molecules
- proteins
- peptides
- amino acids
- nucleotides
- steroids (free diffusion)
- fatty acids
- ions
- gasses (free diffusion)
Ionic signals and signals released via exocytosis can be released either constitutively or evoked. What do these terms mean
Constitutive - passive flow down the concentration gradient
Evoked - channels can be gated
Secreted molecules mediate 4 forms of signalling, what are they and what are they used for (hint = paracrine etc)
Paracrine signalling: Only affect cells in the immediate environment. The signal is terminated by:
- Uptake into neighbouring cells
- Destruction by extracellular enzymes
- Sequestration by ECM
Autocrine signalling: Similar to paracrine but is confined to a specific cell type
Synaptic signalling: a specialised subtype of paracrine signalling
Endocrine signalling: secretion of hormones into the blood. Specificity maintained by only target cells having adequate receptors
(Signals that use gap junctions or gases do not need receptors)
Specificity of signalling can be achieved by either Synaptic signalling or Endocrine signalling. Compare these two methods
Synaptic:
- Arises from the physical location of the signalling site and the receptor
- Therefore, diversity of neurotransmitters is small
- Short distance (the synapse itself)
- Fast
- Receptors are low affinity
Endocrine:
- Arises from the combination of different signalling molecules being recognised by many different receptors
- Therefore a wide range of signals + receptors are needed
- Long distance
- Slow
- Receptors are high affinity
Match the type of receptor to the function:
a) Generate new signals inside the cell (second messengers)
b) Allow flow of ions across membranes
c) Modify existing molecules to generate new signals
d) Changes expression of genes
- Steroid
- Ionotropic
- Kinase
- Metabotropic
a) Metabotropic
b) Ionotropic
c) Kinase
d) Steroids
Name the two types of ionotropic receptor and the types of ions they effect
Excitatory - Influx of positive ions
Inhibitory - Influx of negative ions
What is the general function of metabotropic (G-protein-linked) receptors?
They act indirectly to regulate the activity of a plasma-membrane-bound target protein such as an enzyme or an ion channel.
The intermediate between the receptor and the target is a trimeric G-protein
What happens when a ligand binds a metabotropic receptor i.e. it is activated (in relation to the alpha, beta and gamma subunits)
Ligand binding causes the ALPHA subunit to release GDP for GTP causing:
1) Activation of the ALPHA-subunit
2) Release of the BETA/GAMMA-subunits
Ligand binding to a metabotropic receptor causes a series of changes such as a) ALPHA-subunit activation and b) BETA/GAMMA-subunit release. How do these above changes affect the cell
a) Activation of the ALPHA-subunit alters enzyme activities and changes concentration of intracellular signals (2nd messengers)
b) Release of BETA/GAMMA-subunits sometimes causes modifications to ion channel activity
How is signalling from metabotropic receptors terminated
Hydrolysis of GTP to GDP
Kinase receptors are either enzymes themselves or associated with enzymes. Most have a transmembrane domain with a ligand binding site outside the cell and enzyme activity inside the cell.
What happens when a ligand binds a kinase receptor (in relation to phosphorylation)?
1) Kinase receptors phosphorylate themselves
2) Their signal is amplified via a series of phosphorylation reactions
3) Signals are terminated via the action of phosphatases
How do steroid receptors work
1) Steroids freely diffuse across the plasma membrane
2) Once inside they bind to intracellular receptors, activating them
3) All steroid receptors bind to specific DNA sequences
4) Ligand binding activates gene transcription causing a 2 step response
5a) Direct transcription of a small number of genes
5b) These genes activate other genes and produce a secondary response
How fast are the 4 receptors response times (relatively) and what are they limited by
Ionotropic - Very fast. Limited by:
- receptor pore size
- diffusion gradient
Metabotropic - Relatively fast. Limited by:
- number of enzymatic reactions in the cell
Kinase - Relatively fast. Limited by:
- number of enzymatic reactions in the cell
Steroid - Relatively slow. Limited by:
- speed of gene transcription
Receptors can be targets for drugs in either an agonistic or antagonistic fashion. What do these terms mean in this context and what are the 2 types of antagonism (hint = steric / function)
Agonist: Mimic the natural ligand for the receptor and thus activate it even in the absence of the natural signal
Antagonist: Block the action of the natural ligand inhibiting the action of the receptor
There are 2 types of antagonist:
- Direct antagonism: directly compete with ligand for binding
- Allosteric antagonism: Inhibit receptor function by binding at a different site
Development of the kidney involves a variety of signalling molecules relaying information between the ureteric bud and the metanephrogenic mesenchyme. What are some signals and their function in ureteic branching
TGFb + BMP4: Elongation
BMP7: Go Straight
BMP2: Keep Out
GDNF: Branch
Define ‘weak emergence’
Weak emergence is essentially the overall effect of a combination of different interactions in a biological system. An example is kidney development that utilises a variety of different signals and receptors to stimulate growth.
Match the stage of kidney development to what’s happening:
a) Specification of the intermediate mesoderm into the nephrogenic mesoderm
b) Nephron mesoderm divides into nephron progenitor cells
c) Simultaneous with b), the UB grows and branches
d) UB induces nephron progenitors to differentiate into specific cell types
e) Forms the distinct structures of the kidney such as glomerulus and renal tube
f) Development of blood vessels
- Nephron maturation
- Vascularisation
- Kidney specification
- Ureteric bud formation
- Nephron formation
- Reciprocal induction
a) Kidney specification
b) Nephron formation
c) UB formation
d) Reciprocal induction
e) Nephron maturation
f) Vascularisation
What is the definition of a drug?
a chemical that produces a biological effect when given to a living organism
What additional criteria do the FDA outline when considering drugs
- its structure must be known
- a drug is not a nutrient or essential dietary requirement
This separates drugs from medicines
The advent of DNA technology has led to the introduction of many drugs that are broadly named biopharmaceuticals. What 3 biological mechanisms do these include?
- Enzymes and blood components
- Hormones
- Humanised monoclonal antibodies (Mab)
What 2 major principles govern the therapeutic use of drugs against disease
- Selectivity: selective action on the target tissue
- Specificity: this interaction between drug and target should be unique/specific (usually unmet = side effects)
What is the definition of a receptor in the context of drug administration
any target molecule with which a drug has to combine in order to elicit its desired effect
What are the 4 recognised drug targets
- Receptors
- Ion channels
- Enzymes
- Transporters (carrier molecules)
The AFFINITY of a drug to bind to its target can be quantified in terms of an equilibrium constant: Ka from the Hill Langmuir equation:
[AR]/[RT] = [A]/Ka // [A]/Ka +1
What does each symbol stand for
[AR] = drug receptor complex concentration
[RT] = total number of receptors concentration
[A] = concentration of drug
Ka= Equilibrium constant (mol/l) for drug A binding to R
In the context of drugs, what is the equilibrium constant
The concentration of a drug which occupies 50% of the available receptors. The smaller its value, the higher the affinity of the drug.
What is the definition of efficacy
the ability of an agonist, once bound to the target, to elicit an effect
What is the difference between FULL agonists and PARTIAL agonists
full: elicit the maximum response from a tissue
partial: cannot elicit the maximum response no matter how much drug is applied
What is the definition of an antagonist in relation to efficacy and affinity
Drugs that bind with high specificity to a receptor but do not produce a response. They possess affinity but no efficacy
Give the definition of:
a) Competitive reversible antagonism
b) Competitive irreversible antagonism
c) Allosteric modulators
a) Bind reversibly to the same site as the agonist
b) Same but bind irreversibly
c) Drugs that bind to a site distinct from the agonist binding site of a receptor but modulate the agonist response (can +ively or -ively affet response)
