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
What are afferent neurons
Receiving information
What are efferent neurons
Giving out information
Describe sensory transduction
- stimulus
- Receptor
- Change in permeability
- Change in membrane potential
- Generation of an action potential
- Propagation of action potential to CNS
- Integration pf information by CNS
What are generator potential
- Potentials generated from the receptor that don’t reach the threshold.
- They trigger action potentials.
- They decrement during conduction while action potentials don’t
different types of sensory receptors
- Mechanoreceptors - mechanical force - touch
- Pain receptors - tissue damage
- Thermoreceptors
- Chemoreceptors - dissolved chemicals - smell and taste
- Photoreceptors - light
There are different subtypes of receptors
2 sensory receptor adaptation
Tonic and phasic
What is tonic adaptation
Tonic sensory input adapts slowly to a stimulus and continues to produce action potentials over the duration of the stimulus
What is phasic adaptation
Rapidly adapting. Generator potential diminishes quickly but the stimulus last longer.
What is a receptive field
- Area in which stimulation leads to response in a particular sensory neurons
- Receptive fields change depending where they are in the body.
What is two point discrimination
Is the ability to discern that two nearby objects touching the skin are truly two distinct points, not one
What is flexion reflex
A withdrawal reflex, a spinal reflex intended to protect the body from damaging stimuli
Functions of the autonomic nervous system
- Contraction/relaxation of smooth muscle
- Exocrine and endocrine secretion
- Control of the heartbeat
- Steps in intermediary metabolism
- Not under conscious control
Autonomic nervous system structure
Has an extra synapse in the autonomic ganglion (swelling of cell bodies) before it reaches target organ/tissue.
Neurons before the ganglion are called preganglionic neurons. Neurons after are called postganglionic neurons
2 branches of the autonomic nervous system
Sympathetic (fight or flight) and parasympathetic (rest and digest)
Neurotransmitters of the sympathetic nervous system
preganglionic transmitter: acetylcholine
postganglionic transmitter: noradrenaline
Except: Adrenal glands /sweat glands
Neurotransmitter of the parasympathetic nervous system
Preganglionic transmitter: acetylcholine
Postganglionic transmitter: acetylcholine
Innervation of adrenal glands
Has no postganglionic neuron, just releases adrenaline and noradrenaline
Receptors of the sympathetic branch
alpha and beta adrenoceptors
Receptors of the parasymmpathetic branch
muscarinic ACh receptors
What is a postganglionic varicosity
A synapse, a swelling of synaptic vesicles where neurotransmitters are released.
What is the sympathetic chain
- Fused autonomic ganglion to make a chain
- Make synapse with post synaptic neurons
Length of neurons in the parasympathic nervous system
Has long pre ganglionic neurons to target organs, from the brain stem and sacral region. Then a short postganglionic neurons.
What is the autonomic tone
The general activity rate of the autonomic nervous system, both the sympathetic and parasympathetic. It is always going.
Examples of the autonomic tone
- Blood vessel controlled by the sympathetic tone
- Heart is controlled by the vagal tone
Control of the autonomic nervous system
- Sensory fibres
- Interneurons (in neural circuits in hypothalamus,
brainstem/spinal cord) - Sympathetic and parasymapathetic pre/postganglionic
neurones - Effector organ
Examples of autonomic reflexes
- Fight or flight response
- Salivary
- Vomiting
- Defecation
What is the autonomic nervous system controlled by
- The hypothalamus
- Stimulation of different parts of the hypothalamus produces different autonomic responses
Affect of the parasympathetic nervous system on they eye
- Pupillary light reflex and accommodation.
- Accommodation reflex, changing the lens shape
What is the pupillary light reflex
-Pupillary light reflex controls the diameter of the pupil
What is the accommadation reflex
-Accommodation reflex, changing the lens shape by contracting or relaxing the ciliary muscle in response on focusing on an object either far away or close
Affect of sympathetic nervous system on the eye
Pupil dilation-arousal/stress
What is Pupil dilation-arousal/stress
Pupil size increases in proportion to the difficulty of a task.
Two types of muscle contraction
Isometric and isotonic
What is isometric muscle contraction
An increase in tension while there is no change in length
What is isotonic muscle contraction
Tension remains the same but lengths shortens when overloaded
3 types of muscle
- Cardiac
- Smooth
- Skeletal
Structure of cardiac muscle
- Myocytes are 15 mm in diameter, 100 mm length
- Linked together via intercalated disks
- Electrically coupled via gap junctions
Properties of cardiac muscle
- Striated
- Show myogenic activity
- Cells are electrically coupled
- Controlled by autonomic nervous system and hormones
Properties of smooth muscle
-Muscle of internal organs
-Maintains a steady level of tension (tone)
-Produces slow long lasting contractions
-Linked together by
mechanical and electrical junctions
-No striations
-Very plastic: can adjust length
Smooth muscle different patterns of contraction
Can be:
- fully contracted most of the time
- be partially contracted
- Physically active (contracts then relaxes)
- relaxed most of the time
Different units of smooth muscle
Single unit and multi-unit
What is multi unit smooth muscle cells
Multi unit act independently to their neighbor, controlled by separate varicosities
What is single unit smooth muscle cells
All the smooth muscle cells are controlled by 1 varicosity
Structure of skeletal muscle
- Striated due to alignment of sacromeres
- Sacromeres make myofibrils
- Myofibrils make muscle fibres
What is the sliding filament mechanism
Actin and myosin slide over each other
What does force produced by muscle depends on
- Number of active muscle fibres
- Frequency of stimulation
- Rate at which muscle shortens
- Cross sectional area of the muscle
- Initial resting length (There is an optimal length)
What is T tubules in muscle contraction
Where the action potential goes down when muscles are fired.
What is the sarcolemma
The plasma membrane of the muscle. It is an excitable membrane.
What is the sacroplasmic reticulum (SR)
Membranous sac filled with calcium
What is a triad
- Where the T tubule and sarcoplasmic reticulum meet.
- Found at the A and I band junction
2 fibres in sarcomere
Actin (thin filament) and myosin (thick filament)
Sources of ATP for muscle contraction
- Phosphocreatine
- Glycolysis
- Oxidative phosphorylation
- Anaerobic yield
Stages of the cross bridge cycle
- Tropomyosin prevents the myosin head from attaching to the actin
- Calcium ions cause the tropomyosin to pull away from the binding site on the actin molecule
- Myosin head can attach to the actin
- Phosphate is released and mysoin head changes conformation resulting in the filaments to slide past each other
- ADP is released
- ATP binds and causes the actin and myosin to unbind
- ATP is hydrolysed causing the myosin head to return to resting position
- Cycle repeats
Where is calcium obtained in the muscle
-Opening of voltage gated Ca2+ channels following depolarisation (SK, SM, C)
-Opening of intracellular Ca2+ release channels on SR
(SK, SM, C)
-Ca2+ entry from SR (action of hormones etc)
(SM)
Acetycholine receptors in skeletal muscle
Nicotinic receptors (ionotropic)
How is contraction in muscles terminated
-By calcium removal
1. Small amount of Ca2+
is extruded from the cell
2. Most taken up into the SR
by a SERCA-type pump
How is calcium released in smooth muscle
Hormones and neurotransmitters leads to the release of calcium in the SR
Define external respiration
The exchange of oxygen and carbon dioxide between an organism and the external environment
Define breathing
The process by which air is inhaled into the lungs through muscle contraction and exhaled due to muscle relaxation
Define ventilation
The exchange of air between lungs and the atmosphere so that oxygen and carbon dioxide can be exchanged within the alveoli
3 sections of respiratory control
- Reflex/automatic (brainstem)
- Voluntary/behavioural (motor cortex)
- Emotional
What area controls inspiration in automatic control
PreBotC
What area controls expiration in the automatic control
RTN/pFRG
How did scientists find the areas that control breathing
They cut out regions until breathing stopped
Where does voluntary control of breathing take place
Motor cortex:
-Midbrain
Humans have remarkable degree of voluntary control
-
What is the breaking point in breathing
Voluntary control cannot be maintained when stimuli such as PCO2 or H+, become too intense
Emotional control of breathing
Overrides everything.
Controlled by the limbic system.
What information do respiratory centres receive
Information from:
- Chemoreceptors
- Protective reflexes
- Pulmonary stretch receptors
2 types of pulmonary stretch receptors
- Slowly adapting Pulmonary Stretch Receptors (long term)
- Rapidly adapting Pulmonary Stretch Receptors (short term, on them off quickly)
Where are the slowly adapting Pulmonary Stretch Receptors located
Smooth muscle of the bronchi and trachea
What stimulates the slowly adapting Pulmonary Stretch Receptors
Stretch of the muscles in the bronchi and trachea
What do the slowly adapting Pulmonary Stretch Receptors signal
Signal lung volume to the brain at any moment.
The function of slowly adapting Pulmonary Stretch Receptors
- Inhibit inspiration and lengthen expiration
- Important in regulating respiratory rhythm
Where are rapidly adapting pulmonary stretch receptors located
In the epithelial cells in the larnyx, trachea and airways
What to the rapidly adapting pulmonary receptors respond to
Respond to mechanical/chemical environment of lung (irritants)
Function of rapidly adapting pulmonary stretch receptors
- Constrict airway & promote rapid shallow breathing
- Promote cough in trachea and larynx
- Respond to gradual collapse of lungs (atelectasis) by causing an augmented breath or sigh every 5 minutes
What is lung compliance
- Magnitude of change in lung volume from a change in transpulmonary pressure.
- The greater the lung compliance the easier it is to expand the lungs
2 major factors of lung compliance
- Stretch-ability of the tissue
2. Surface tension within the alveoli (lower surface tension the greater the lung compliance)
What lowers surface tension in the alveoli
Secreting pulmonary surfactant
What is pulmonary surfactant what causes secretion
- A mixture of phospholipids and protein
- Secreted by type II alveolar cells
- A deep breath (e.g., sigh) increases secretion (by stretching the type II cells)
What causes respiratory distress syndrome in newborn
Deficiency in pulmonary surfactant
What are protective reflexes and what are the 2 types
- A group of responses that protect the respiratory system from irritants.
1. Cough reflex
2. Sneeze reflex
2 types of chemoreceptors
- Central chemo-receptors
- Peripheral chemo-receptors
Where are central chemoreceptors located
Mdulla oblongata
Function of central chemoreceptors
- Respond to changes in the brain’s cerebrospinal fluid
- Stimulated by increased PCO2 directly, or via associated changes in hydrogen ion concentration
Where are peripheral chemoreceptors located
Carotid bodies and Aortic bodies
What do peripheral chemoreceptors respond to
Respond to changes arterial blood:
- Decreased PO2 (hypoxia)
- Increased PCO2 (hypercapnia)
- Increased [H+] (acidosis)
What causes inspiration
Initiated by activation of the nerves to the inspiratory muscles (external intercostal muscle)
What causes expiration
- Passive: Inspiratory muscles relax and lungs recoil
- Active: activation of expiratory muscles (internal intercostal muscles)
How are the lungs and the intercostal muscle joined together
Joined by a vacuum seal in the pleural cavity by intrapleural fluid.
Pleurae cover the lung and the wall of the thorax
What is visceral pleura
A thin layer of epithelium covering each lung
What is Parietal pleura
Lines inner surface of the walls of the thorax
Whats happening to a normal lung at rest
- Elastic recoil of the chest wall tries to pull the chest wall outwards
- Elastic recoil of the lung creates an inward pull
What is pneumothorax
- The collection of air in the pleural space
- The lung collapses due to elastic recoil
What is transpulmonary pressure (Ptp)
-Difference in pressure between the inside and outside of the lungs within the thorax.
- A positive pressure keeps lungs inflated
Palv>Pip
What is pressure in the lungs called
-Pressure in the lungs is alveoli pressure (Palv)
What is pressure out of the lungs in the thorax called
intrapleural pressure (Pip)
Equation for flow into lungs
Pressure difference between atmosphere and alveoli/ resistance
What is boyles law
Pressure is inversely proportional to volume
What happens in isnpiration
- Muscles of the chest and diaphragm contract
- Ribs pulled up
- Intrapleural pressure lowers
- Transpulmonary pressure increases
- Lungs expand
What happens during expiration
- Muscles of chest wall and diaphragm relax
- thorax diminishes, Pip increases
- Transpulmonary pressure decreases
- Elastic recoil > Transpulmonary pressure
- Lungs passively recoil to their original dimensions
What measures lung volume
Spirometer
What does lung volume vary to
Height Age Sex Health Physical training
2 pulmonary function tests
FEV1 is the volume expired in the first second
FVC (forced vital capacity) is the total volume expired
What is daltons law
In a mixture of gases, the pressure exerted by each gas (the partial pressure) is the pressure that the gas would exert if it were the only gas in the volume occupied by the mixture.
What is partial pressure dependent on
Concentration
What is the pressure of the atmosphere
760 mm Hg
What is the pressure of the lungs
47 mm Hg
What is anatomical dead space
Volume of gas within the conducting airways
What is physiological dead space
Volume of gas not involved in gas exchange
When does diffusion occur
Net diffusion of a gas will occur from a region where its partial pressure is high to a region where it is low.
What is the respiratory quotient (RQ)
The ratio of carbon dioxide production to oxygen consumption
How is oxygen transported in the blood
- 2% dissolved in plasma
- 98% bound to haemoglobin
Structure of haemoglobin
-Protein made of 4 subunits:
2α and 2β
-A haem group is attached to each subunit
When is haemoglobin saturated and less saturated
- Saturated when PO2 is high (in alveoli), haemoglobin binds O2
- Less saturated when PO2 is low (in tissues) haemoglobin releases its stored O2 reserves
What is the Bohr effect
Carbon dioxide (CO2) shifts the haemoglobin saturation curve to the right
- causes haemoglobin to release more O2, less saturated at the same partial pressure
- CO2 diffuses from venous blood into alveolar space allowing more O2 to load onto haemoglobin
- Temperature and acidity promote O2 unloading
Affect of carbon monoxide on haemoglobin
- Haemoglobin has a greater affinity to CO than O2
- CO displaces O2 from haemoglobin
- The haemoglobin saturation curve is shifted to the left
- Less oxygen unloaded at the same partial pressure, oxygen saturation is higher
Transport of CO2 in the Blood
- 5% dissolved in plasma
- In red blood cells, most CO2 is converted to carbonic acid by the enzyme carbonic anhydrase. Carbonic acid immediately dissociates into H+ and HCO3 -
- HCO3- ions are transported out of red blood cells in exchange for Cl- ions 70 %
Chloride shift
Role of the trachea
Deliver air to the lungs from the mouth and nose
How many lobes are there in each lung
- 3 lobes in the right lung
- 2 lobes in the left lung
Role of the bronchi and bronchiole
To distribute air throughout the lungs
2 types of bronchioles
Terminal and respiratory
What are respiratory bronchiole
Bronchioles that give rise to alveoli where gas exchange takes place
What is classified as the respiratory tree
The branching structures of the airways from the trachae to the alveoli
4 sections of the respiratory system
- Upper airways
- Lower airways
- Conducting airways
- Respiratory zone
What does the upper airway comprise of
Mouth, nose , pharynx and larynx
What does the lower airway comprise of
From the top of the trachea to the alveoli
What does the conducting zone comprise of
-From the mouth and nose to the end of the terminal bronchioles.
Function of the conducting zone
- Conducts air but does not exchange gas
- Warms (or cools) and moistens the air
- Defends against microorganisms and chemicals by cilia
- Provides low resistance
Where is the greatest resistance in the conducting zone
Greatest resistance is in the trachea, lowest is in the bronchioles.
What does the respiratory zone comprise of
-Respiratory bronchioles and alveoli
Defence mechanisms of the airways
- Cilia
- Mucus
- Macrophages
- Constriction of bronchioles
What are cilia
Hair-like projections that line epithelial cells that beat upwards towards the pharynx
Function of mucus
To trap particulate matter and bacteria. It is wafted to the pharynx where is it swallowed. This is the mucus elevator
What is mucus secreted by
Glands and epithelial cells lining the airways
Function of macrophages
Phagocytose particles and bacteria
What causes asthma
- Chronic inflammation of the airways
- Inflammation causes smooth muscle to contract increasing airway resistance
- This increases work of breathing
What causes bronchitis
- Persistent inflammation of the bronchial walls
- Increases in mucus secreting cells and loss of ciliated cells
- Excess mucus is produced
- Obstruction of the airways, hindering breathing and oxygenation of blood
Function of the respiratory zone
- Provides oxygen
- Eliminates carbon dioxide
- Regulates blood pH
- Traps and dissolves blood clots arising from systemic veins
- Influences arterial concentrations of chemical messengers
What is pulmonary circulation
- Large network of capillaries in the alveolar walls
- Includes blood pumped from the right ventricle through the lungs to the left atrium
- Under low pressure but high flow
What makes the gas exchange efficient
- Each alveoli is associated with many pulmonary capillaries, large surface area
- Inhaled air is brought into close proximity to “pulmonary” blood, thin barrier
- Moist surface
What is ventilation
The amount of gas getting to the lungs
What is perfusion
The amount of blood getting to the lungs
What is ventilation perfusion mismatching
Defects in total lung ventilation perfusion ratio.
What are ideal ventilation perfusion ratios
You want:
- Regions of low ventilation should have low blood flows
- Regions of high ventilation should have high blood flows (base of lung)
What alters Ventilation-perfusion ratios
Hypoxia sensing cells that constrict vessels to stop blood supplying areas with poor gas exchange
Where does greatest perfusion and ventilation takes place
- Happens at the bottom of the lungs
- arteriole pressure > veinus pressure > alveolar pressure
- Blood pressures increase down the lung’s vertical axis
What is flicks law
Rate of diffusion is directly proportional to surface area
What is emphysema
- A disease characterised by destruction of the alveolar walls and collapse of the lower airways
- The lungs undergo self-destruction by proteolytic enzymes secreted by leukocytes
- Adjacent alveoli fuse, reducing total surface area available
- Increased airway resistance due to inflammation
2 diseases apart of the chronic obstructive pulmonary disease (COPD)
- Chronic bronchitis
- Emphysema
Why are the number of deaths caused by chronic obstructive pulmonary disease increasing
Air pollution
Symptoms of hypoxia
Mildly euphoric state, rapid loss of critical judgement, slowed thinking and muscular weakness
Why is there higher barometric pressure at the equator than expected
Extra solar radiation causes an upwelling of atmosphere at the equator hence the column of air is higher
What causes maximal oxygen consumption to fall
A lower inspired oxygen partial pressure
How does hypoxia affect physical performance
Reduced physical power and greatly increased fatigue
How does hypoxia affect mental performance
- More arithmetic errors
- Reduced attention span
- Increased mental fatigue
- Night vision reduced
How does hypoxia affect sleep
- Frequent awakenings
- Unpleasant dreams
due to periodic breathing (cycles of breathing then not breathing)
What causes periodic breathing
- There is increased ventilation to take in more oxygen and remove CO2
- Partial pressure of CO2 falls, so there is reduced breathing
- Due to reduced breathing there is a lower partial pressure of O2
Affect on pH at high altitudes
Blood becomes more alkaline as hyperventilation reduces partial pressure of CO2 in the blood
The difference in people living at high altitudes and people living at low altitudes
Highlanders have increased numbers of erythrocytes and greater oxygen carrying capacity.
What happens in high altitude acclimatisation
A transient increase in erythrocyte concentration occurs through reduction of plasma volume
3 high altitude diseases
- Acute mountain sickness
- High altitude pulmonary edema
- High altitude cerebral edema
What is acute mountain sickness
- Headache, breathlessness, fatigue, nausea
- Usually altitudes higher than 3000 m
- Last 2 or 3 days
- May be brain swelling
- Rapid descent reverses symptoms
Treatment for acute mountain sickness
Acetazolamide -a carbonic anhydrase inhibitor.
This increases excretion of HCO3- helping to reduce alkalosis
What are the symptoms of high altitude pulmonary edema
- Laboured breathing, reduced exercise tolerance
- Dry cough that may give frothy blood stained sputum
- Rapid breathing and heartbeat
- Raised body temperature
Causes of high altitude pulmonary edema
Pulmonary hypertension (high blood pressure) due to hypoxic pulmonary vasoconstriction exposes pulmonary capillaries and the capillary walls fail.
Treatment of high altitude edema
Move to low altitude, will give a rapid cure
Symptoms of high altitude cerebral edema
-Potentially fatal
-Confusion, rapid mood changes, hallucination
Loss of control of body movement, Coma
-Only rapid descent will cure this
Why can birds withstand high altitudes
- Counter current exchange system as air passes in one direction only due to a 2 cycle breath
- Have a uniquely thin blood gas barrier
- Powerful heart
Why is counter current exchange effcient
- Concentration gradient for O2 maintained along length
- Most oxygenated blood meets air with highest PO2
Role of connexin 26 (Cx26) in breathing
- Is a CO2 sensor
- CO2 binds to Cx26, releases ATP and signals to breath
- Birds have a more sensitive Cx26 as birds have a lower resting PaCO2 than mammals
Function of the heart
- Delivers oxygen
- Removes CO2
- Delivers hormones
- Important to homeostasis
Why is the heart a double circulatory system
-Made of the pulmonary system and systemic system
Where does the tricuspid valve sit
Sits between right ventrical and right ventrical
Where does the bicuspid valve sit
Between left atrium and left ventricle
What is sytole
Ventricular contraction
What is diastole
Relaxation permits filling of the heart
When is the tricuspid valves opened and closed
Opened - diastole
Closed - systole
When is the bicuspid valve opened
Opened - diastole
Closed - systole
When are the pulmonary valve and aortic valve opened and closed
Opened - systole
Closed - diastole
How to calculate cardiac output
stoke volume x heart rate
What is the cardiac output of humans
5 L.min^-1 of blood
What is the stroke volume of a human
~70ml of blood in a single beat
What is starling’s law of the heart
The energy of contraction is a function of the length of the (cardiac) muscle fibres.
How does blood volume affect starlings law of the heart
An increase in blood volume increases stroke volume, the greater the stretch and the greater the force to pump blood
What happens if you overstretch the heart
Over stretching reduce the stroke volume
Stages of the spread of the heartbeat
- Heart is myogenic
- Depolarisation is intiated by the sinoatrial node (SA)
- Travels to the atrioventricular node (AV)
- Travels down the bundle of His to purkinje fibres
What causes depolarisation in the heart
- Depolarisation is often generated by a reduction in permeability to K+ and an increased permeability to Na+.
- Depolarisation may also be produced by an increase in Ca2+ permeability.
What part of the nervous system is the heart controlled by
Sympathetic activity - increases heart rate
Parasympathetic activity - decreases heart rate
Why does the heart have a long refractory period
As calcium goes against potassium
Why does the heart have a long refractory period
To prevent tetanus in cardiac muscle
What is tetanus
When the muscle is contracted and stays contracted
What are myocytes
- Muscle cells with a single nucleus.
- Striated, often branched
How are myocytes electrically coupled
- Connected by tight junctions and coupled through connexins
- Contraction is activated by the entry of Ca2+
- The action potential can propagate from cell to cell through the electrical connections
Components of the ECG recording
Systole = QT interval Diastole = RR - QT
Basic structure of blood vessels
- Lumen
- Tunica intima (interna):
- endothilium
- connetive tissue - Tunica media:
- Elastic tissue
- Smooth muscle - Tunica adventitia (externa)
- collagen
Differences between veins, capillaries and arteries
- Arteries are under high pressure and have thicker smooth muscle.
- Veins have valves due to a lack of pressure
- Capillaries are just a single endothelial layer
What elasticity depend on
Thickness of the elastic tissue
Why are blood vessels elastic/ what is the windkessel effect
- When there is high pressure the elasticity allows the walls to stretch increasing volume and flow
- When the heart finishes the beat the elastic fibres recoil maintaining blood flow
Role of smooth muscle
- To control resistance and make sure blood if flowing to the correct place.
- Contraction of smooth muscle reduces diameter
3 factors that determine resistance
-Length of blood vessels
(longer it is the more resistant)
-Viscosity of blood
-Radius of blood vessels
Blood flow is laminar, what does laminar mean
- Different lines where blood flows at different rates in a blood vessel.
- Fastest flow is in the centre and slowest on the outside.
Equation for resistance in blood
R=8nl/πr^4
n= viscosity
l= length
r= radius
What happens to flow when velocity becomes to high
- Laminar flow breaks up and flow becomes disordered.
- Become turbulent flow
- There is increased resistance
- Tends to lead to ednothelial damage
Function of capillaries
- Exchange of blood gases and metabolites
- Generation of an equilibrium between plasma interstitial fluid
Why are capillaries one cell thick
- Short diffusion distance
- Minimises resistance to diffusion
Equation for diffusion flux (J)
J = P.A(Ci-Co) P= permeability coefficient A= area of exchange (Ci-Co)= concentration gradient
Permeability of Lipid soluble molecules
They can diffuse easily through capillary cell membranes
Permeability of hydrophobic molecules
Travel through the pores via paracellular route
Permeability of molecules > 60kd
- They are not transferred and many plasma proteins are retained.
- Important in equilibrium between plasma and extracellular fluid
2 compartments of extracellular fluid
- Interstitial fluid
- Plasma
There is an equilibrium between the 2 compartments, this is determined at the sites
What are starlings forces
- Hydrostatic pressure
- Oncotic pressure
They maintain equilibrium between plasma and interstitial fluid
What is the role of hydrostatic pressure
Responsible for the loss of fluid from the plasma
What is the role of oncotic pressure
- Responsible for reabsorption of fluid into the plasma
- Is constant at 25mmHg
- Caused by large proteins above 60KDa
How does hydrostatic pressure change in the capillary
- High pressure 35mmHg at the arteriolar end
- Lower pressure 15mmHg at the venular end
How to work out filtration pressure
Filtration pressure = hydrostatic pressure – oncotic pressure
Role of the lymphatic system
Samples the blood for foreign particles by taking up excess fluid
How does the muscle pump enhance venous return
- When muscles contract it squeezes the vein pushing blood to the heart
- Muscle pump is proportional to demand. When your muscle contracts you need more blood, so muscle pump delivers more blood
How does the respiratory pump enhance venous return
An decrease in intra-thoracic pressure lowers right atrial pressure, resulting an increase in venous return.
What part of the nervous system controls the heart
Parasympathetic and sympathetic of the autonomic branch
What part of the nervous system controls blood vessels
Sympathetic nervous system
Role of the parasympathetic system in the heart
- Innervation of pacemakers and atrial muscle
- Has a negative chronotropic effect
Role of the sympathetic system in the heart
- Innervation of pacemaker and all cardiac muscle
- Has a positive chronotropic effect
- Has a positive inotropic effect
What is a negative chronotropic effect
-Slows the heart through the action of acetylcholine
What is a postive chronotropic effect
-Speeds the heart through the action of noradrenaline
What is a positive inotropic effect
An increase in contractility of the myocardium through the action of noradrenaline enhancing Ca2+ release in myocytes
Vasoconstriction by Sympathetic nerve fibres
Sympathetic nerve fibres enhance contraction of smooth muscle. Action potentials release noradrenaline.
Role of vasoconstriction
- Control overall resistance of the systemic circulation
- Regulate flow to particular organs
How does the sympathetic nervous system cause vasoconstriction
Noradrenaline acts on a1 and a2 receptors to mobilise Ca2+ in smooth muscle cells
Describe blood flow to the brain
Overall blood flow to the brain is the same but there are changes to alter blood flow to different areas in the brain
What determines blood pressure
Mean arterial blood pressure = cardiac output x total peripheral resistance
Where are baroreceptors found
In the aorta and carotid sinus
What is the carotid sinus
Thin wall dilatation located at the proximal end of the carotid artery which goes up the neck to the head
What is the baroreceptor reflex
A homeostatic mechanism that helps maintain blood pressure.
Stages of the barorecptor reflex
Baroreceptors sends stimulate to vasomotor centres which effects the parasympathetic and sympathetic nervous system
Baroreceptor reflex with low blood pressure
Vasomotor centres cause stimulation of the sympathetic system and inhibition of the parasympathetic nervous system. Cardiac output increases and an increase in total peripheral resistance (TPR) and increase in venous return.
Equation for blood pressure
Blood pressure = cardiac output (CO) x total peripheral resistance (TPR)
How does the sympathetic system affect work output
Sympathetic system increases the work that the heart does at any filling pressure
How is blood volume regulated
Secretion of renin by the kidney
What does renin do
Turns Angiotensinogen -> Angiotensin 1 -> Angiotensin 2
Angiotensin 2 affect on circulation
-Rapid: powerful vasoconstricter increasing peripheral resistance and increase venous tone
-Slow: Secretion of aldosterone
Increases retention of Na+ (cation of ECF) which reduces excretion of water, Increases thirst, Increasing ECF and plasma volume
increases filling pressure
Role of stretch receptors
They sense filling pressure and help regulate extracellular fluid.
Where are the stretch receptors found
Found in the atria
What happens when stretch receptors are stimulated
- Releases atrial natriuretic peptide/factor (ANP)
- Causes renal excretion of NA+, resulting in reduction of extracellular fluid volume
- Also causes secretion of anti-diuretic hormone (ADH), which reduces extracellular fluid
- ADH is also a vasoconstrictor
What is vasomotor tone
The degree of how much a blood vessel is constricted. Vasomotor tone controls resistance.
What happens when blood become hypoxic or blood flow is blocked
- This results in an increase of metabolites such as adenosine which causes validations and increase flow.
- Metabolites oppose the vasoconstrictor sympathetic nerve fibres, causing vasoconstriction
How does filling pressure determine cardiac output
Filling pressure influences stroke volume, which influences cardiac output
What is a haemorrhage
Rapid loss of blood, which results in a fall of blood volume and a fall in filling pressure. Cardiac output fall, resulting in reduced blood pressure
Haemorrhage: immediate corrections
from baroreceptor reflexes
- modify heart rate and contractility through the sympathetic and parasympathetic nervous system
- Veins and arterioles constrict to raise total peripheral resistance
Haemorrhage corrections from secretion of renin
- Constricts arterioles and veins
- Increase TPR
- Restole filling pressure
Haemorrhage on hydrostatic pressure
Reduced hysdrostatic pressure which results in reabsorption through the capillary bed. This restores blood volume.
Haemorrhage secretion of erythropoietin
Restore red cell count
4 different classes of haemorrage
- Class 1: 15% of blood volume, no change in vital signs
- Class 2: 15% - 30% of total blood volume, trachycardia
- Class 3: 30% - 40% of blood volume, blood pressure drops, heart rate increases, peripheral hypoperfusion (shock) not enough oxygen and nutrients to body tissue
- Class 4: > 40%, aggressive resuscitation is required to prevent death.
How to clinically treat a haemorrhage
- Treat blood loss
- Give fluids
- Monitor oxygen saturation
- Monitor the filling pressure (Left atrial pressure)
What is needed for exercise
- Increased blood supply
- Raise cardiac output and balance changes in peripheral resistance
- Increase coronary blood flow
What causes an increase in blood supply to skeletal muscle
- Vasoconstriction in peripheral tissue
2. Vasodilation in muscle blood vessels
Affect of adrenaline from sympathetic nervous system
- Acts on α-receptors causing vasoconstriction to peripheral tissue.
- Adrenaline also acts on b2 receptors, which have a vasodilator action.
Affect of noradrenaline from the sympathetic system
- Acts on α-receptors causing vasoconstriction to peripheral tissue.
- Causes smooth muscle to constrict
Major role played by local vasodilator metabolites: Match blood flow to metabolic needs
- Electrical actvity releases K+ which relaxes vascular smooth muscle
- Increase ATP metabolism, Adenosine is an important paracrine vasodilator
- In exercise anaerobic respiration → lactate production
The change of pH leads to vasodilatation
Increased blood flow to skeletal muscle by Co2
Lactic acid and CO2 cause vascular sphincter to relax increasing flow in the capillary bed
4 things that cause vasodilation
- Adenosine
- K+
- Noradrenaline
- Adrenaline
3 things that cause vasoconstriction
- Sympathetic tone
- Angiotensin II
- ADH
Why is starling law not followed in exercise
At high filling pressures, stroke volume no longer increases with increasing filling pressure, and there isnt a greater cardiac output.
How does cardiac output increase
- Principally through an increase in heart rate
- CO cannot be sustained through an increase in SV alone
- Increase in heart rate reduces filling time (diastole)
- Protects from overfilling due to an increase in venous return from muscle pump
Thermoregulaation during exercise
You need to remove excess heat by sweatig or cutaneous vasodilation.
Problems with cutaneous vasodilation in thermoregulation
Cutaneous vasodilation reduces peripheral resistance and will
divert blood from muscles
Coronary circulation during exercise
- Heart must increase its own blood flow
- Blood flow to myocardium is however intermittent, occurring principally in diastole.
- Vasodilator metabolites – principally adenosine - ensure that blood flow is matched with O2 consumption
Why are pulmonary pressures low during exercise
Low pulmonary blood pressures are permitted because of the low resistance of the pulmonary circulation.
What is responsible for low pulmonary circulation resistance
- Short distance: To keep the diffusion path for O2 and CO2 short so that gas exchange works effectively
- Large diameter: highly compliant
What is the principle regulator of the pulmonary circulation
- Oxygen; low oxygen levels result in vasoconstriction
- It matches perfusion to ventilation by shutting dow dead areas
- Switches blood supply away from regions of the lung that are not well ventilated – owing to disease – and helps maintain effective oxygenation of blood
Characteristics of rods
- High sensitivity
- Low temporal resolution
- Low acuity
- Only see in one wavelength
Characteristics of cones
- Lower resolution
- Higher temporal resolution
- High acuity
- See 3 wavelengths
What is the photopigment in the eye
Rhodopsin as G protein coupled receptor
What are photoreceptors in the dark
They are depolarised with Na+ ion gated channels open
What happens to photorecptors in light
They are hyperpolarised with Na+ ion gated channels closed
Phototransduction cascade summary
- Light
- Cis-retinal to trans-retinal in rhodopsin
- Transducin activated
- cGMP phosphodiesterasee activated
- cGMP levels fall
- cGMP-gated ion channels close
- Photoreceptors hypolarised
Ganglion cells have a receptive field
Ganglion cell is a type of neuron located near the inner surface of the retina of the eye. Receptive field is a portion of sensory space that can elicit neuronal responses when photoreceptors stimulated. Receptive field is the arrangement of photoreceptors going to a ganglion cell
2 types of receptive fields of ganglion
- On centre: stimulation when light hits the centre
- Off centre: stimulation when light hits the surrounding
Different illuminations for an On-centre ganglion
- Centre illumination: intense stimulation, light hits the centre
- Annular illumination: no stimulation, light hits the surrounding
- Diffuse illumination: constant stimulation, whole ganglion cell is lit
What is convergent signalling
Where receptive field centres overlap
How is hypolarisation converted to depolarisation for an action potential
-In on centre bipolar cells light causes less glutamate to be released due to
hypolarisation in photorecptor causes depolarisation in the bi polar cell
-In off centre bipolar cells darkness causes glutamate to be released. This causes hypolarisation in bipolar cells.
Role of the retina
Contrast detector: it detects variations in light across a visual scene, rather than the absolute level of light
What do on-centre ganglion cells signal
Rapid increases in light intensity
What do off-centre ganglion cells signal
Rapid decreases in light intensity
What are Lateral geniculate neurons
Relay center in the thalamus for the visual pathway
Lateral geniculate neurons have concentric visual fields
-On-centre field
(off-surround)
-Off-centre field
(on-surround)
2 pathways of Lateral geniculate neurons
M channel -analysis of movement
P channel -analysis of fine detail and colour
Receptive fields of simple cells in visual cortex
- Specific retinal position
- Discrete excitatory and inhibitory regions
- Specific axis of orientation
- All axes of orientation are represented for each part of the retina
- Light has to hit in the same orientation in the retina
Complex cells
- Must be the same orientation
- Firing when bar of light is moving
3 photoreceptors
- Rods
- Cones
- Light sensitive ganglion cells (ipRGC)
What is the opsin presnet in light sensitive ganglion
Melanopsin - an ancient opsin
Role of light sensitive ganglion cells
- Circadian clock entrainment
- Pupilary dilation
- low acuity images
What is age-related macular degeneration and what is its treatment
- Gap in visual field due to death of photoreceptors.
- Photoreceptor transplantation
Units for sound decibels sound pressure level
A logarithmic scale called decibels sound pressure level.
How does the basilar membrane varies along its length
- Membrane is thicker and floppy at the apex
- Membrane is thin and taught at the base
Why does the width vary of the basilar membrane
- Different positions of basilar membrane vibrates at different frequencies creating standing waves.
- Base responds to high frequencies
- Apex responds to lower frequencies
How is sound converted to electrical impulses
As the basilar membrane in the cochlea vibrates, it presses against the tectorial membrane causing the hair cells to move leading to changes in electrical potentials
What is frequency tuning of hair cells
Hair cells are different at different positions along the cochlea. They are optimised for different frequencies of sound.
How is sound amplified
There are motor proteins on the outer hair cells which lengthen and shorten the hair cells when it hears a sound. This amplifies the vibration.
What is otoacoustical emissions
Sounds produced by the ear
What is the motor protein called
- Prestin
- When cilia gets pressed by sound. This causes a current and a change in membrane potential which causes a confrontational change.
Demonstrating the role of prestin in electromotility and hearing
499 mutation removes electromotility from single hair cells. Hair cells cant change length.
What causes signal transduction
- Hair cells are linked together by tip links.
- There are ion channels in the tips, which allow potassium in when cilia move
What are stereocilia
The sites of mechanotransduction
What is the endocochlear potential
+80mV
The potential that provides the driving force on K+ to give inward current,
In the stria vascularis
Why are potassium ions used in signal transduction in the ear
- Causes the smallest change in the cytosolic concentration as it is the must abundant ion in the cytosol
- Influx and extrusion of K+ are energetically inexpensive as they both occur down an electrochemical gradient
What is the resting membrane potential of a hair cell in cochlea
-65mV
Provides a driving force for potassium to enter the hair cell. Potassium then leaves the hair cell and it is recycled
How many genes are associated with hearing loss
- 14 genes
- May affect molecule in hair cells
- May affect potassium recycling
How does deletion of Cx26 affect hearing
- Cochlea doesnt develop properly if deleted at day 1
- Reduction of endocochlear potential affecting potassium recycling
- Hair cell degeneration
- Affects electromotility of outer hair cells, no amplification
Role of hair cells in the utricle and saccule
They detect head motion, by deflection of hair cells.
What are the afferent neurons of hair cells
- Spiral ganglion neurons creating auditory nerve
- Each SGG innervates only one inner hair cell, but 10 SGC innervate one hair cells
What is the auditory nerve
A bundle of nerve fibers that carries hearing information between the cochlea the brain
How are spiral ganglion cells tuned
-The are tuned to frequency of the hair cells they innervate.
What do spiral ganglion cells in the ear encode
Intensity and frequency
How do cochlear implant work
Feed an electrode around the cochlea that stimulate the ganglion cells depending on frequency
Role of different neurons in cochlea nucleus
Different neuron cells detect different parts of sound
Auditory pathway to the brain
- Cochlea
- Chochlear nucleus
- Medial superior olive
- Brain, auditory cortex
Role of the medial superior olive (MSO)
- There are 2 MSOs, one on each side
- MSOs get input from both ears
- Sound from source reaches one ear before the other, giving a delay
- Gives rise to direction of sound
What gives direction of sound
- Neurons only fire when inputs from the left and right are simultaneous
- So depending on the positioning of the neuron and time of conduction to the neuron, only specific neurons fire depending on direction of sound
What is Wernicke’s area in the brain responsible for
Language comprehension
What is Broca’s area in the brain responsible for
Language production
