Physiology and metabolism Flashcards
What does cell signalling control
- Growth
- Differentiation and development
- Metabolism
What happens if signalling goes wrong
- Cancer
- Heart disease
- Diabetes
- Neurological diseases etc.
What are the principles of signalling
- signal: information beyond the membrane
- Receptor: information detector
- Amplification
- Response: chemical changes and/ or changes in gene expression
It is a universal property of living cells
What is an agonist
Ligands that stimulate the pathway
What are antagonists
Lingans that inhibit the pathway
What is direct contact signalling
A ligand on the signalling cell binds a receptor on the target cell. Common in tissue development
What is gap junction signalling
Intracellular connections that allow exchange of small signalling molecules and ions, co-coordinating metabolic reactions between cells. e.g. electrical synapses
What is autocrine signalling
- The ligand induces a response only in the signalling cell. (self stimulation).
- Most autocrine ligands degrade in the extracellular medium.
Examples of autocrine signalling
- Eicosanoids are autocrine ligands derived from fatty acids and exert complex control
- Common feature of cancers: auto production of growth hormones stimulates cell proliferation
What is paracrine signalling
- The ligand induces a responce in target cells close to the signalling cell.
- Diffusion of the ligand is limited. It is destroyed by extracellular enzymes.
Stages of neuro-muscular junctions and paracrine signalling
- Nerve impulse
- Stimulates synaptic vesicles to fuse with the cell membrane
- Releases acetylcholine
- Acetylcholine stimulates channels opening, allowing ion exchange
- The muscle twitches and acetylcholinesterase degrades the acetylcholine
What is endocrine signalling
The ligand is produced by endocrine cells and is carried in the blood, inducing a response in distant target cells. The ligands are often called hormones
A problem with different types of signals
Some ligands fall into more than 1 category.
How is specificity provided in cell signalling
- Cell-type specific expression: only certain receptors are present or molecules downstream of the receptor are only present.
- High affinity interactions: There is a precise molecular complementarity between
ligand and receptor, mediated by non-covalent forces.
What is the association rate how do you calculate it and what is its units
Is the rate of concentration change (Ms^-1)
Association rate = k+[R][L]
k+ = the second order
association rate constant (M^-1s^-1)
R= receptor
L= Ligand
What is the dissociation rate how do you calculate it and what is its units
Is the rate of concentration change (Ms^-1)
Dissociation rate = k-[RL]
k- = the first order (s^-1) association rate constant R= receptor L= Ligand
What happens when rate of association and rate of dissociation are equal
They are at equilibrium
Calculations for equilibrium constant, its units and what does it show
- keq = k+/k- = [RL]/[R][L]
- Keq has units of M^-1 (per molar)
- Keq gives affinity of the molecules for each other
Calculations for dissociation equilibrium constant (Kd) and its units
Kd = k-/k+ = [R][L]/[RL]
-Has units of M (molar, or moles per litre)
How does affinity effect specificity
- High affinity interaction are specific
- Low affinity interactions are less specific.
How are signals amplified
Enzyme cascades:
- The receptor or an enzyme associated with the receptor is activated.
- This now catalyses the activation of a second enzyme, which activate multiple molecules of a third enzyme, etc.
- Happens within milliseconds
What happens when a single is continuously present
- The signal transduction pathway becomes desensitised.
- when the signal falls below a threshold level, the system regains sensitivity
What is cross talk
When signalling pathways share common components and one signal may affect more than one pathway
What is signalling integration
If multiple signals are given, the cell produces a unified response
Steps of EGFR signalling
- highly specific, high affinity interaction
- differential EGFR expression
epithelial cells; hematopoetic cells - amplification by the MAPK enzyme cascade
- desensitisation by dephosphorylation of EGFR
- cross-talk and integration with other signalling pathways
- : altered gene expression
Example of a receptor which is an enzyme
Insulin receptor (IR). Binding of ligand activates the enzyme activity.
Hormones that regulate blood glucose levels and there roles
- Insulin (Pancreatic)
- Glucagon (Pancreatic)
- Epinephrine (adrenal)
- Cortisol (adrenal)
Which hormones lower blood sugar levels
Insulin
Which hormones increase blood sugar levels
Glucagon, epinephrine and cortisol
Where is insulin and glucagon produced
Secreted from the islets of langerhans.
α cells: glucagon
β cells: insulin
What happens to insulin receptors following translation
- Enter the ER membrane
- Associate into dimers
- Exported to the cell surface via golgi complex
- During intracellular transport, the proteins are processed by cleavage, each into an α and a β subunit.
- At the plasma membrane they are displayed as trans-membrane proteins
How are insulin receptors activated
- Insulin binds
- Causes allosteric change in IR
- Brings cytosolic domains close
- Auto phosphorylation happens
- Allowing activation
Define a ligand
An extracellular substance that binds to a cell-surface receptor and initiates signal transduction that results in intracellular activity
Define a receptor
A protein that binds and responds to the first messenger
Insulin signalling steps for growth factor
- Activated IR phosphorylates and activates the insulin receptor substrate 1 (IRS-1)
- Activated IRS-1 is bound by the adaptor molecules Grb2 and Sos.
- Sos converts inactive (GDP-bound) Ras to active (GTP-bound) Ras.
- Ras recruits Raf and activates protein kinase activity.
- RAF phosphorylates and activates MEK kinase. MEK phosphorylates and activates mitogen-activated protein kinase (MAPK) called ERK .
- ERK migrates to the nucleus and alters gene expression.
What also recruits the same MAPK cascade as insulin receptors
EFG also modulates the same genes
What is another function of IRS-1 other than the growth factor
Regulates glucose
Define a secondary messenger
A small molecule, not a protein, whose concentration can change rapidly. They relay signals from receptors to target molecules.
How is glucose regulated through IRS-1
- IRS-1 recruits and activates phosphoinositide 3-kinase (PI-3K).
- PI-3K phosphorylates the membrane to produce PIP3 is a second messenger.
- PIP3 recruits PKD1 which activates protein kinase B (PKB)
Cellular response to insulin within minutes and within hours
- Within minutes:
- Increase uptake of glucose into muscle cells
- Altered glucose metabolism - Within hours:
- Increased synthesis of glycogen
- Increased synthesis of triacylglycerols
- Increased mitogenesis
Termination of the fast Ras-independent pathway
A PIPs-specific phosphatase (PTEN) removes the phosphate at the 3 position of PIP3 to convert it into PIP2.
PDKI and PKB can no longer be recruited to the plasma membrane, shutting off signalling through PKB.
What can go wrong with insulin signalling
Type 1 and Type 2 diabetes.
Cant respond to insulin or produce it, resulting in high blood sugar levels.
How to reverse type 2 diabetes
- Increased exercise with a very strict diet reduces diabetic symptoms and restores insulin sensitivity.
- This suggests that desensitisation of insulin responses follows prolonged exposure to high sugar levels
How is BMI calculated
BMI= weight (kg)/height^2 (m^2)
Cause of obesity/gaining weight
The intake of excess calories, more than the body consumes
3 mechanisms for dealing with excess calorific intake
- Conversion of excess fuel to fat
- Increase locomotor activity
- Thermogensis: convert fuel to heat
What is the lipostat theory
- Eating behaviour is inhibited when body weight exceeds a certain value
- Postulates that energy consumption increases above the set point
What regulates lipostat model
- A soluble fat called Leptin is released into the bloodstream by adipose tissue
- Leptin binds to the hypothalamus and changes feeding behaviour
How was leptin discovered
- Found in inbred mice
- Leptin is produced from Lep^OB (obese) gene
- Mice with Lep^ob have more and larger adipocytes (fat cells), dont produce leptin
- Lep^ob mice is corrected with leptin
- Lep^ob mice display the physiology and behaviour of starvation and some similarities to type 2 diabetes
How can type 2 diabetes be caused genetically in mice
- Depends on the leptin receptor gene
- Mice with Lepr^db gene are obese and insulin resistant
- They have no leptin receptor
Stages of leptin signalling
- Leptin binds to the receptor
- Dimerises Lep-R
- Which generates sites that recruit JAK (Janus kinases)
- JAK phosphorylates Lep-R
- Phosphorylated Lep-R recruits STATs
- JAK phosphorylates STATs causing them to dimerise
- Dimerised STATs activate transcription factors that modulate gene expression
What are the effects of leptin
- Suppression of appetite
- Stimulation of the sympathetic nervous system
which: increases blood pressure, heart rate, and thermogenesis
Cross talk between insulin and leptin
Leptin also signals in liver and muscle cells, making them more sensitive to insulin.
Function of erythropoietin (EPO)
It is a hormone cytokine that controls the development of erythrocytes (red blood cells) from precursor cells in the bone marrow.
Uses of EPO
- Used on people who have sever anaemia and cannot receive a blood transfusion
- Women receiving chemotherapy for cancer in the ovaries who have low blood haemoglobin levels
- Used by athletes in doping
How does EPO signal
- Via JAK-STAT pathway using STAT5
2. Following JAK autophophorylation EPO signalling can access a RAS-dependent pathway
Basic structure of G-protein coupled receptor (GPCR)
-Extracellular domains E1 and loops E2-4 -Trans-membrane domains H1-H7 (helix 1-7) or TM1-7 -Cytosolic domains Loops C1-C3 and C4 tail -Also know as serpentine receptors (looks like its wrapped around the membrane)
How does a small ligand bind to a (GPCR) and what does it cause
- GPCRs fold into a tertiary structure resembling a barrel and forms a cavity. The cavity is where the small ligand binds.
- Changes the relative orientations of the TM helices (a twisting motion)
How do bulky ligands bind and what does it cause
- They bind to the extracellular loops or the N-terminal tail.
- Ligand binding alters the conformation of the TM domains, and reveals amino acids in the cytosolic domains for activating G-proteins.
How are bound G proteins activated
- They are inactive when bound to GDP
- Active when bound to GTP
- Ligand binding induces nucleotide exchange, the replacement of GDP with GTP at Gα
What is a G-protein
A trimer of α, β, and γ subunits (Gα, Gβ, and Gγ)
What happens after G protein activation
- G-protein dissociates from the receptor to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer.
- These now modulate the activity of other intracellular proteins
How does the G protein become inactive again
- Gα has a slow GTP hydrolysis activity.
- Regenerates the inactive form of Gα-GDP
- Also causes reassociation with a Gβγ dimer to form the ‘resting’ G-protein
Physiological responses to fight of flight
- Liberation of metabolic energy sources for muscular action
- Acceleration of heart and lung function
What stimulates the fight or flight response
Epinephrine and cortisol from the adrenal glands
Role of cortisol in fight or flight response
- Increases blood sugar through gluconeogenesis
- Suppresses the immune system
Role of epinephrine in fight or flight response
- Binds to a variety of adrenergic receptors which are GPCRs
- Binding to α-adrenergic receptors inhibits insulin secretion, stimulates glycogenolysis, and stimulates glycolysis
- Binding to β-Adrenergic receptors triggers glucagon secretion, and increased lipolysis by adipose tissue
Signal pathway of epinephrine
- Epinephrine binds a β-adrenergic GPCR receptor, Gαs is activated and stimulates adenylate cyclase
- Increases cAMP levels and induces a variety of proteins (one of these is protein kinase A) for glycogen break down and increased heart rate
How is epinephrine signalling terminated
- Adenylated cyclase acts as a GAP on Gαs
- GAP is a GTPase-Activating Protein which converts the Gα to its inactive form
Glucagon signalling
GLUCAGON: higher blood sugar via a GPCR and a second messenger (cAMP), stimulating glycogen breakdown
Effect of cholera toxin (CTx)
- Has a catalytic A chain (CTxA1)
- It enters the cytosol
- CTxA transfers a specific ribose group on to a specific arginine on Gαs
- GTP cannot be degraded and adenylate cyclase is turned ON, permanently
- There is an increased efflux of Na+ and water into the intestine
- Death by dehydration
Structure of rods
- Has an outer segment containing 1000 discs.
- Each disc is a closed sac of membranes with embedded photosensitive rhodopsin molecules.
Structure of rhodopsin
- A specialised GPCR
- Made of opsin linked to 11-cis-retinal (light absorbing prosthetic group)
Describe cis-trans isomerisation during light capture
- Alternating single and double bonds form a polyene with a long unsaturated network of electrons that can absorb light energy
- Light absorption causes cis-trans isomerisation around the C12 and C13 double bond
- Nitrogen of the lysine moves 5 Å (0.5nm)
- Activates rhodopsin
Light energy is converted into atomic motion within a few picoseconds
Describe activation of rhodopsin (GPCR)
- Light absorption by the retinal alters the conformation of GPCR
- Inactive rhodopsin becomes activated metarhodopsin II
- Metarhodopsin stimulates nucleotide exchange on the α-subunit of a specific heterotrimeric G protein called transducin (Gt).
- Each activated metarhodopsin II activates ~ 100-500 transducins (Gt)
2 G-proteins that affect adenylate cyclase
- Gs: stimulates adenylate cyclase
- Gi: inhibits adenylate cyclase
What does the Gt do
stimulates cGMP phosphodiesterase
Effect of stimulated Gt
- Gαt (GTP) stimulates cGMP phosphodiesterase which removes cGMP from cGMP-gated ion channels
- Gated ion channels close hyperpolarising the membrane.
- A light stimulus has been converted to a change in the electrical charge
What is rhodopsin sensitivity
- Peak absorbance at 500nm
- Responds to a single photon
- 5 response is required for the brain to register a flash
How is activated rhodopsin terminated/made insensitive
- Closed cGMP gated ion channels, reducing influx of Ca++
- Ca++ leaves the cell by Na+/Ca++ antiporters and Ca++ concentration in the cell falls
- Low Ca++ activates guanylate cyclase: cGMP levels rise: channels re-open and there is an increased concentration of Ca++ in the cell
Insensitivity caused by Prolonged cGMP-gated channel closure
High light insensitivity in rhodopsin
- Light-activated rhodopsin can be phosphorylated by rhodopsin kinase
- This reduces the activation of transducin. The higher the phosphorylation, the lower the ability to activate transducin
Very high light insensitivity in rhodopsin
Arrestin binds to fully phosphorylated rhodopsin: and this stops activation of transducin.
How many colour pigments can humans typically see
3 - trichromats
Each cone cell expresses only one visual pigment (red, green and blue)
Some women can see 4 pigments
What is colour tuning
- Photoreceptors captures light of a different wavelength and responds to a different wavelength
- This is due to amino acid differences (charge differences) which alters the electronic environment that surrounds the 11-cis-retinal chromophore.
- Chromophore responds to different fequencies of light
How many pigments do colour blind people see
- 2, they are dichromats and have difficulty distinguishing similarly sized objects where lightness varies in an unpredictable manner
- Or 3 where where the spectral sensitivity of one of the cones has shifted.
John dalton colour blind experiment
- John dalton was colour blind and postulated he had a blue pigment in his eye that absorbed red light
- When he died there was no blue pigment in his eye
- He had a deletion of the gene encoding the MW pigment
Selective pressures for trichromacy and why are there still colour blind people in the population
- Selective pressure: Colour vision may of co-evolved with production of yellow, orange and red pigments in maturing fruit
- Dichromats tend to spot animals quickly
What does Sildenafil citrate
do and what is its side effects
-Sildenafil is a potent inhibitor of cGMP phosphodiesterase
-Sildenafil citrate also inhibits PDE-6.
PDE-6 regulates blue-green colour discrimination in the retina
-A side-effect of sildenafil citrate can be blue-tinged vision
Stages of nitric oxide activating guanylate cyclase
- The gas nitric oxide diffuses across the plasma membrane
- Binds to the soluble receptor guanylate cyclase (GC) haem group, causing a conformational change
- The activated receptor converts GTP into cGMP
- cGMP is a second messenger that alters activity of target proteins
What is nitric oxide used to treat for
- Angina (chest pain due to reduced blood supply to the heart).
- Nitric oxide an endothelium-derived relaxing factor, relaxes vascular smooth muscle
- Nitric oxide is released from nitroglycerine
When do blood vessels dilate, how do they dilate and why do they dilate
- Dilate under high pressure
- Dilation occurs when smooth muscle relaxes
- Dilation increases the volume of the vessels and lowers blood pressure
How is nitric oxide (NO) stimulated in vivo
- Nerves in blood vessel walls respond to high blood pressure and release acetylcholine (Ach)
- Acetylcholine binds to receptors on endothelial cells and increases Ca^2+
- Ca^2+ is a secondary messanger and activates nitric oxide synthase
- Nitric oxide synthase converts arginie to citrulline and nitric oxide
Effect of cGMP for smooth muscle
- cGMP activate protein kinase G in smooth muscle.
- Phosphorylates the myosin light chain causing muscle cells to relax
- Blood vessels dilate, increasing volume and reducing pressure
Other functions of nitric oxide
- Control of capillary dilation
- Control of peristaltic movement through the gut
- Regulation of glomerular capillary pressure
- Regulation of blood flow in the adrenal glands
- Regulation of muscle contraction and blood flow in the corpus cavernosum (the erectile tissue in a penis)
Not all responses are by protein kinase G, but some are cGMP-gated ion channels or cGMP-dependent phosphodiesterases
Nitric oxide synthase isoforms and functions
-Neuronal isoform;
development of the nervous system
-Inducible isoform;
produces large amounts of NO* as a defence mechanism used by macrophages
-Endothelial isoform;
controls vascular tone, insulin secretion, and regulates angiogenesis
Other sources of NO
Amyl nitrate inhalation spray which vapourises to generate NO. The NO dilates vascular smooth muscle.
What are Phosphodiesterases (PDEs)
- Cyclic nucleotides that important secondary messengers.
- They cleave the 3’,5’-cyclic phosphate moiety of cAMP and/or cGMP to produce the corresponding 5’ nucleotide
Role of Phosphodiesterase type 5 (PDE5).
Specifically cleaves cyclic guanosine monophosphate (cGMP).
What drug targets PDE5
sildenafil citrate
What does sildenafil citrate
do
- Is a potent inhibitor of cGMP phosphodiesterases.
- It is most active against phosphodiesterase 5.
- PDE-5 causes blood vessels to constrict in erectile tissue of the penis
- It is viagra
What is oestrogen, how many types are there
-Oestrogen is the primary female sex hormone
-They are steroid hormones
-There are 4 types:
E1, E2, E3 and E4
What is oestrogen synthesised by
Androgens (male sex hormones) such as testosterone by the enzyme aromatase
Structure of oestrogen receptors (ER)
- Has an N-terminal transactivation domain, a DNA-binding domain, and a hormone-binding domain that can bind oestrogens.
- Has a dimeric chaperone protein called Hsp90.
Function of Hsp90
Maintains the oestrogen receptor in a soluble state
What is an Oestrogen-bound ER
- Transcription factor
- ER-oestogen complex is released by Hsp90,enters the nucleus and binds oestrogen response elements (EREs) as a dimer.
- Oestrogen-responsive genes are transcribed
Why is there no amplification in oesrogen-activated ER
ONE protein is both receptor and effector: there are no amplification steps via protein cascades or via second messengers
Physiological roles of oestrogen receptors
- Reproduction function
- Cardiovascular system
- Immune system
- Central nervous system
- Skeletal system
How can 1 receptor/effector regulate so many different processes and 4 different oestrogens
- There are multiple isoforms of the ER.
- There are two different forms of the ER (α and β)
- They can form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers
- There are splicing variants as well
what happens when GPER is stimulated
Oestrogen binds GPER and multiple pathways are stimulated:
① ligand-independent activation of ER
② release of EGF via Ca2+ as a second messenger and ③ stimulation of the MAPK signalling pathway via interaction with Grb2 and gene expression changes
What drug is used to treat ER+ breast cancer
Tamoxifen
How does tamoxifen work
- It inhibits oestrogen receptors by not allowing them to take on there active conformations
- also causes cells to remain in the G0 and G1 phases of the cell cycle
Why are some breast cancers resistant to tamoxifen
GPER can stimulate oestrogen-responsive growth independently of ER, and tamoxifen does not inhibit GPER
What 3 systems are present in the nervous system
- Sensory system
- Integrating system
- Motor system
What does the integration system do
Make decisions from sensory and previous experiences
3 parts of a neuron
- dendrites
- soma (cell body)
- Axon
Which direction does conduction take place
Unidirectional from dendrites to soma to axon
Role of dendrites, axon, myelin and terminals
Dendrites: increase surface area to receive inputs
Axon: carries information over long distances
Myelin: coats axon and improves conduction
Terminals: Output region transmitter
Why are there different types of neurons
Different neurons perform different functions based of shape and size
What is anterograde transport
From soma to terminals
What is retrograde transport
From terminals to soma
What does axonal transport require
- Hydrolysis of ATP
- Microtubules
What is the Gila
A support system. There are different Gila cells:
- Astocyte
- Microglial cells
- Oligodendrocyte
What does the microglial cell do
Acts as a scavenger cleaning up cellular debris. Also launches immune response
What does the astrocyte do
Corrects ionic environment, provides metabolic fuel for neurons and mops up transmitters
What does oligodendrocytes do
Forms the myelin sheath
What is ganglion
A collection of nerve cells
What lead to vertebrate encepthalization
Fusion of ganglia -> Brain/spinal cord -> vertebrate encepthalization (increase in complexity of the brain)
How to work out Encephalisation quotient and what does it show
Encephalisation quotient = Brain weight / body weight
Shows relative brain size
What does the central nervous system comprise of
Brain and spinal cord
What does the peripheral nervous system comprise of
- Autonomic (involuntary) Nervous System
- Somatic (voluntary) Nervous system
What are the different spinal cord segments
- Cervical
- Thoracic
- Lumbar
- Sacral
What does medial mean
Towards the middle
What does lateral mean
Towards the edge
What does dorsal mean
Towards the back
What does ventral mean
Towards the gut
Brain structure
Forebrain and brainstem.
What is the forebrain composed of
Diencephalon and telencephalon
What is the brain stem composed of
Midbrain mesencephalon and hindbrain rhombencephalon
What is the meninges
Membrane covering the brain and spinal cord. Brain is suspended in a jacket of cerebrospinal fluid (CSF)
3 layers of meninges
- Tough outer layer: dura matter
- Arachnoid mater
- Pia mater
Role of cerebrospinal fluid (CSF)
-Removes waste products
Supplies brain & sp cord with nutrients
-Buffers changes in blood pressure and protects brain
-Supplies brain with fluid during dehydration
-Allows the brain to remain buoyant
Regions of the brain stem
Medulla - respiration, cardiovascular function
Pons - links with cerebellum, modifies medulla output
Cerebellum - balance, gait, fine movement, posture
Midbrain - visual, audio information, motor control, sensation
Components of the diencephalon
Thalamus- integrates sensory information
Hypothalamus- autonomic control, appetitive drives reproductive behaviour, homeostasis, endocrine control
What are the 2 hemispheres linked by
Corpus callosum
What is Somatotopic organisation of the cortex
Where the cortex has been labelled where different sections control different parts of the body
What is the resting membrane potential of a cell
-70mV
What is hyperpolarising
Making the membrane potential more negative
What is depolarising
Making membrane potential more positive
What does a resting potential require
- A semi-permeable membrane
- Ionic concentration gradients and ionic permeabilities
- Metabolic processes
Concentrations of sodium (NA+) and potassium (K+) at resting potential
- More potassium inside the cell than outside.
- Less sodium inside the cell than outside of the cell
What happens at equilibrium of the cell
- There is a balance between K+ ions moving in and out of the cell,this occurs at the resting potential
- Chemical gradient = electrical gradient
How to calculate resting potential for ideal membrane (Ek)
Ek = (RT/ZF)log10([K+]out/[K+]in)
R = gas constant, T = temperature, F =Faraday constant Z = valency
What happens when the concentration gradient of the ions decrease
Electrical gradient decreases to maintain equilibrium
What ion is the membrane impermeable to ideally
Sodium (Na+)
Why is membrane potential is usually less negative than Ek
This is because the Cell membrane not completely impermeable to Na+ (Na+ moves in)
and there is K+ leakage (K+ moves out)
What maintains ionic gradients
ATP-dependent ion pumps
3 properties of an action potential
Unidirectional
Fast
All or nothing
What affects speed of an action potential
Temperature
What causes an action potential
The influx of sodium (Na+) into the neuron by voltage gated channels.
How to calculate driving force
Concentration gradient + electrical gradient
What cause voltage-gated Na+ channels to open
- Synaptic transmission
- Sensory neurons
- Inherent properties – cells that spontaneously depolarise in cycles.
- Experimental
Why is Na+ channel opening is regenerative
There is a cycle:
- Na+ channels open
- Na+ influx into neuron
- Depolarisation, which causes Na+ channels open
What is an action potential threshold
Certain threshold level of stimulus is needed to generate an action potential. All or nothing, cant get half an action potential.
2 things that cause repolarisation
- Voltage-gated K+ channels open - Therefore K+ ions move out of the neuron
- Na+ channels close
2 types of refractory period
- Absolute – a second action potential cannot be generated regardless of strength or duration of stimulus
- Relative – a second action potential can be generated at a greater cost in strength or/and duration
Where are axon potentials initiated
axon hillock
What affects action potential conduction
Axon diameter
Bigger diameter = faster conduction
What is saltatory conduction
Depolarisation at a node of ranvier which causes a sodium influx and the next node of ranvier depolarised downstream. There are lots of sodium channels at the nodes.
Energy requirements of action potential
-Do not need immediate energy source to fire
action potentials.
-Therefore do need ATP in the long term (to run pumps).
-Most of the energy budget (1/3) in the brain is used in action potentials
What is a synapse
A junction where information is passed from one neuron to another (or to muscle)
What is there a lot of present in the synapse
Mitochondria, to generate energy for the synapse
2 types of synapses
Electrical and chemical
What is a chemical synapse and what is its key characteristics
- Chemicals are released from the synaptic neuron to modulate postsynaptic neuron.
- There is a delay
- One way
- Plastic
What is an electrical synapse
- There are ion channels called connexons.
- There is no delay
- Can be 2 way
- Little plasticity
What does plasticity mean
The ability for it to change throughout its life
Name some chemical neurotransmitters
Amino acids:
- GABA: main inhibitory neurotransmitter
- Glutamate: main excitatory transmitter
Others:
- Acetylcholine
- Nitric oxide
Where are chemical synapses found
Chemical synapses are found on dendritic spine, soma, axon hiloc
- axodendritic
- axosimatic
- axoaxonic
How is neurotransmitter packaged in vesicles?
- A proton gradient drives vesicle filling
- Exchange of hydrogen ions provide energy to pump neurotransmitters in co-exchangers
- There are different types of neurotransmitters exchangers
Where are peptide neurotransmitters synthesised and where are they transmitted too
In peptide based neurotransmitters, neurotransmitters are packaged in the cell body and sent to the terminals
4 basic steps of neurotransmitter release
- Docking
- Ca2+ entry
- Vesicle fusion (exocytosis)
- Recycling of vesicles (endocytosis)
Process of docking of vesicles to the membrane
SNAP and SNARE proteins anchor vesicles to the presynaptic membrane
Process of Ca2+ entry into nerve terminals
- An action potential depolarised nerve terminals via voltage-gated Na+ channels
- Opens voltage-gated Ca2+ channels
- Ca2+ moves into the nerve terminal down its electrochemical gradient
Process of vesicle fusion (exocytosis)
-Ca2+ binds to one of the SNARE proteins (synaptotagmin) leading to fusion of docked vesicles and release of neurotransmitters
Important features of Ca2+-dependent transmitter release
- Transmitter release requires binding of multiple Ca2+ ions
- Transmitter release occurs very quickly after Ca2+ entry
- Blocked Ca2+ entry blocks synaptic transmission
Process of vesicle recycling
Retrieves vesicle by clathrin, which causes a curvature in the membrane.
What blocks endocytosis (vesicle recycling)
Dynasore, which inhibits dynamin. Leads to rapid synaptic depression
Why are there different types of postsynaptic receptors
- Different types of receptors have different time scales to produce cellular effects.
- They have different time scales
- They produce different speeds of signalling
What is acetylcholine synthesised by
CHAT = choline acetyltransferase
What packages acetylcholine into vesicles
Vesicular acetylcholine transporter(VAChT)
Two types of receptors of acetylcholine
-Nicotinic:
Ionotropic
Permeable to Na+/K+
Fast signalling
-Muscarinic:
Linked to G proteins (Metabotropic), uses second messenger cascade
Slower signalling
Why are neurotransmitters removed from the post synapse
To have maximum impact of postsynaptic effect you want to reduce background activity. They do this by removing the neurotransmitter.
How is acetylcholine recycled
- By AChE = acetylcholinesterase in extracellular space
- ACh -> choline + acetate
- Choline is recycled
- Acetate is excreted
Identifying features of a neurotransmitter
- Must be synthesised in the neuron
- Show activity-dependent release from terminals
- Duplicate effects of stimulation when applied
exogenously (in lab) - Actions blocked by competitive antagonists in a concentration-dependent manner
- Be removed from the synaptic cleft by specific
mechanisms
What is the structure of a peripheral nerve
It is made up of fascicles and blood vessels
What do fascicles comprise of
Fascicle a mixture of myelinated and non-myelinated axons
Where are motorneuron cell bodies found
In the ventral horn of the spinal cord
Affect of upper motor neurons on lower motor neurons
Upper motor neurons activate the lower motor neurons which activate the muscle
What is a neuromuscular junction
Synapse between nerve and muscle
What is 1 motor unit
- 1 motor neuron that makes contact with many muscle fibres.
- Intermingled throughout the muscle
- Motor units are different sizes (number of muscle fibres they connect to)
What happens when the motor unit is activated
-All muscle fibres will contract
Effect of different sized motor units
- Fine control = small motor units
- Coarse control = large motor units
The different types of skeletal muscle and there characteristics
Type 1:
- Slow oxidative (ATP oxidative phosphorylation)
- Contraction speed is slow
- Force generated is low
- Small motor units
Type 2: Fast oxidative (ATP oxidative phosphorylation) Speed of contraction: intermediate Force generated: intermediate Intermediate motor units
Fast glycolytic (ATP through glycolysis)
Speed of contraction: fast
Force generated: high
Large motor units
Why are muscles folded
To increase surface area to fill up with acetylcholine receptors
Neurotransmitter and receptor of neuromusclar junction
Acetylcholine (ACh) and nicotinic receptors which are ion channels (inotropic)
Permeable to Na+, K+ and Ca2+ and depolarise muscle fibres
What is the size principle
Smaller motor units are
recruited first
How to increase force of contraction
- Recruitment of more muscle fibres
2. Temporal summation: increasing the number of action potentials so that they sum together
2 types of temporal summation
Fused tetanus - muscle is continuously contracted
Unfused tetanus - muscle twitches, doesn’t completely relax before the next stimulus
What happens when a muscle fatigues
- Muscle tension decreases per action potential.
- Some muscle fatigue others don’t
Why do muscles fatigue
- Depletion of glycogen
- Accumulation of extracellular K+
- Accumulation of lactate
- Accumulation of ADP+P
- Central fatigue
What sort of fatigue does type 1 muscle show and what does type 2 show
- Type 1 shows little fatigue, they are slow muscles
- Type 2 shows fatigue quickly, they are fast muscles
Stretch receptors in your muscles
- Golgi tendon organs, found in the tendon, detects tension
- Muscle spindles, found in the middle of the muscle. Involved in the stretch reflex. Detects stretch
How do muscle spindles detect stretch
- When a muscle contracts the muscle spindle relaxes.
- When a muscle stretches the muscle spindle also stretches.
- Length of muscle spindle detects change
What is the stretch reflex
Muscle contraction in response to stretching within the muscle.
What is the golgi tendon reflex
- Golgi tendon reflex will reduce muscle contraction to protect the muscle and prevent damage
- Can be overrided
