Health and Disease Flashcards
define pharmacology
the science of drugs and how they act in biological system
What are the 4 main protein targets for drug action?
- receptors
- ion channels
- enzymes
- transporters
What do ion channels do?
they are present on cellular membranes and open in response to environmental cues, which allows the passage of channel-specific ions down a concentration gradient
What are the 2 ways in which drugs can affect ion channels?
blockers and modulators
What do blockers do to ion channels?
they block ion channels and prevent ion movement
What do modulators do to ion channels?
they don’t block the channel, but bind and increase or decrease the chance of the channel opening
What are the 3 ways in which drugs affect enzyme activity?
inhibitors, false substrates, prodrugs
How do inhibitors affect enzyme activity?
they block substrate from binding
How do false substrates affect enzyme activity?
the enzymes produce an abnormal metabolite
How do prodrugs affect enzyme activity?
drugs given to the patient are inactive, so enzymes convert them into active state
What do transporters do?
transport substances across membranes, can be against a concentration gradient- but only ONE side of membrane is open at once
What are the 2 ways in which drugs affect transporters?
inhibitors and false substrates
How do inhibitors affect transporters?
they block activity of the transporter, so it can’t transport substances across the membrane
How do false substrates affect transporters?
an abnormal compound will accumulate at the other side of the membrane
What are receptors?
proteins that typically sit on cell membrane and respond to exogenous cues and relay a signal into a cell to produce a response
What are the 3 ways in which a drug affects a receptor?
agonist, antagonist, modulator
How do agonists affect receptors?
activates the receptor when it binds
How do antagonists affect receptors?
bind to receptor, but produce NO response, and block activity of the receptor by endogenous activators
How do modulators affect receptors?
they bind to elsewhere on the receptor and increase or decrease the ability of the receptor to activate
define receptor
proteins, usually on the surface of a cell which receive and transduce signals
define ligand
something that binds, can be an agonist or antagonist
define agonist
something that binds and produces a response
define antagonist
something that binds and produces NO response
define second messenger
a molecule that relays a signal from a receptor to an effector
define signal transduction
a sequence of second messengers that elicit a biological response
How do receptors work?
- ligand binds to receptor
- causes a conformational change of the receptor protein
- results in a cellular effect
What are examples of cellular effects after a receptor is activated?
opening of a channel, activation of a linked enzymes. recruitment of an effector protein, intracellular transport
What are the 4 main families of receptor?
- ligand-gated ion channels
- G protein-coupled receptors
- Kinase-linked receptors
- nuclear receptors
How do ligand gated ion channels work?
when a ligand binds, it opens the channel, allowing the movement of channel-specific ions
What is an example of a ligand gated ion channel?
acetylcholine and nicotonic receptors
How do acetylcholine and nicotonic receptors work?
- an electrical impulse travels down the pre-synaptic neurone
- this triggers the release of acetylcholine
- acetylcholine acts on nicotinic acetylcholine receptors on the post-synaptic neurone
- this opens the channel, and allows sodium ion entry, which triggers an impulse in the next neurone
What is kinase?
a second messenger and an enzyme
What does kinase do?
it uses ATP to phosphorylate targets, and acts as a switch to turn target on or off and allows other 2nd messengers to bind to phosphorylated target protein
How do kinase-linked receptors work?
- the receptors is on the cell membrane as two halves
- when ligand binds to receptors it brings the two receptors halves into a dimer
- activates kinase activity of the receptors and a cascade and biological response
What is an example of a kinase-linked receptor?
epidermal growth factor receptor
How is epidermal growth factor receptor (EGFR) related to lung cancer?
EGFR can promote cell growth, and some patients with lung cancer may express many more EGFR receptors, so experience more growth
What is a G protein-coupled receptor?
a receptor with 7 transmembrane domains coupled to a G protein
How do G protein-coupled receptors work?
ligand binding activates the G protein bound on the intracellular surface, which interacts with an affector
How are G protein-coupled receptors activated?
- receptor is in resting state attached to G protein
- ligand binds and G protein is activated
- GDP is exchange for GTP by G protein
- GTP bound G protein interacts with the target effector, which causes a response
- the G protein then hydrolyses GTP to GDP and the G protein can dissociate from the effector
What is an example of a G protein-coupled receptor?
muscarinic receptors and smooth muscle contraction
How do muscarinic receptors work?
- muscarinic M3 G-protein coupled receptors are on intestinal smooth muscle
- acetylcholine activates M3 receptors
- the G protein is then able to bind to effector
- contraction of smooth muscle occurs
- therefore, antimuscarinics can be used to treat IBS
How do nuclear receptors work?
- the receptor is NOT associated with the cell membrane, but in the cyotplasm
- ligand enters the cell and binds to receptor in the cytoplasm
- ligand-receptor pair allows it to change conformation and it can move into nucleus
- it then binds to DNA and acts on gene expression
What is an example of a nuclear receptor?
oestrogen receptor
How are oestrogen receptors associated with breast cancer?
some patients with breast cancer may have more oestrogen receptors, so there is more growth
these receptors can be targeted by Tamoxifen
What is blood production controlled by?
multiple protein cytokines (release by WB cells) and growth factors
What detects blood vessel damage?
platelet surface receptors
What do platelets secrete? Why?
soluble factors to activate neighbouring platelets
What is required for a clotting cascade?
multiple blood proteins
What does thrombopoietin do?
regulate production of platelets
What does erythropoietin do?
regulate production of erythrocytes
What are the major precursors of platelets?
megakaryocytes
What kind of cells give rise to haematopoietic precursors of blood cells?
pluripotent stem cells
What creates a bruise?
when blood vessel endotheliums become damaged and blood leaks into surrouding tissues
What is the scientific name for blood clotting?
haemostasis
What 2 stages can clotting be broken down into?
- primary haemostasis
- secondary haemostasis
What happens in primary haemostasis?
platelets form a plug and are attracted to site of damage
What happens in secondary haemostasis?
a blood clotting mechanism is used to transform and stabilise the weak platelet plug into a clot by a fibrin network
What is the 1st step of platelet plug formation?
adhesion
What are the steps of adhesion in platelet plug formation?
- damage to endothelium cells exposes subendothelial tissue which is made up of collagen fibres
- collagen activates platelets and they adhere to these collagen fibres via an intermediate protein called von Willebrand factor (vWF)
- platelets binding to collagen causes a release of ADP and serotonin from their secretory vesicles, resulting in more platelet activation
What is the 2nd step of platelet plug formation?
platelet activation
What are the steps of platelet activation?
- release of ADP and serotonin from vesicles
- this causes change in shape and surface protein expression of platelets
What is the 3rd step of platelet plug formation?
platelet aggregation
What are the steps of platelet aggregation?
- platelets adhere to each other to form a plug
- synthesis and release of thromboxane A2 from arachidonic acid enhances more activation and aggregation
What stabilises the platelet plug?
fibrinogen bridges that form when receptors in the platelet surface become exposed during activation
What causes contraction of the plug?
actin and myosin
What do healthy endothelial cells do?
synthesis and release of Prostacyclin (PGI2) and nitric oxide, which both inhibit platelet activation
What is the scientific name for a clot?
a thrombus
What is a clot?
the transformation of blood into a gel consisting of fibrin polymers that occurs around the platelet plug
What does vessel damage activate?
a cascade of enzyme that results in the activation of an enzyme called thrombin
What does the enzyme thrombin do?
cleaves a protein called fibrinogen into fibrin molecules that create the fibrin network
Sequence of events
clotting factors -> prothrombin -> thrombin -> fibrinogen -> fibrin -> blood clot
What are the overall steps of blood clotting?
- damage to blood vessel lining triggers the release of clotting factors
- formation of the platelet plug and vasoconstriction limits blood flow
- development of the clot and fibrin strands adhere to form an insoluble clot
How is thrombin activated?
activated from prothrombin which then cleaves fibrinogen to fibrin (which is stabilised by activation of factor 8 by thrombin)
What are the steps in activating the clotting cascade for the extrinsic pathway?
- initiated by a tissue factor, not blood protein, on the outside of plasma membrane of cells in the sub-endothelial tissue
- tissue factors activates factor 7 and they both activate factor 10
- generates small amounts of thrombin
- thrombin then feeds back onto the intrinsic pathway to activate components and generate more thrombin
What are the steps of beginning the enzyme cascade in the intrinsic pathway of the clotting cascade?
- clotting factor 12 is activated by contact with collagen
What is the role of the liver in blood clotting?
- produces many clotting factors
- produces bile salts which are required for absorption of vitamin K needed for production of prothrombin
What does thrombin do?
it is an enzyme that recruits the intrinsic pathway and activates factor 5 and activates platelets
How does the protease activated receptor on platelets activate them?
- the enzyme thrombin binds and cleaves the thrombin receptor at a specific site on the N terminus on a platelet
- the cleaved N terminus can then bind and activate the receptor on the platelet
What are examples of clotting disorders?
damage to endothelium (myocardial infarction), clots (deep vein thrombosis), clotting disorders (haemophilia)
define pharmacology
the science of drugs and how they act in biological systems
What are the 4 main protein targets for drugs?
- receptors
- ion channels
- enzymes
- transporters
Which 2 ways do drugs affect ion channels?
blockers, modulators
How do blockers affect ion channels?
they block ion channels and prevent ion movement, paticularly VGNC
How do modulators affect ion channels?
they don’t block but they regulate how easily the channel opens or closes, and may need a lower or higher voltage -> so increase or decrease the chance of the channel opening
Which 3 ways do drugs affect enzymes?
- inhibitors
- false substrates
- prodrugs
How do inhibitors affect enzyme activity?
they block activity by binding to active site
How do false substrates affect enzymes?
they bind to the enzyme and produce an abnormal metabolite
How do prodrugs affect enzymes?
they are drugs in an inactive state and bind to enzymes to be activated
Which two ways do drugs affect transporters?
inhibitors and false substrates
How do inhibitors affect transporters?
blocks activity of the transporter so it can’t move substances across the membrane
How do false substrates affect transporters?
transporter thinks it is a different substrate, so an abnormal compound accumulates
What are the 3 ways in which drugs can affect a receptor?
agonist, antagonist, modulator
How do agonists affect receptors?
they bind to and activate the receptor
How do antagonists affect receptors?
they bind to the receptor and block activity by other activators -> do NOT activate it though
How do modulators affect receptors?
they bind elsewhere on the receptor and increase or decrease the ability of the receptor to activate
define receptor
proteins, usually on the surface of a cell which receive and transduce signals
define ligand
something that binds
define agonist
something that binds and induces a response
define antagonist
something that binds and produces NO response
define second messenger
a relay signal from a receptor to effector
define signal transduction
a sequence of second messengers that elicit a biological response
What are the steps of a basic ligand-receptor interaction?
- ligand binds to receptor
- this causes a conformational change of the receptor protein
- this results in a cellular effect e.g. opening of a channel
What are the 4 main types of receptor?
- ligand-gated ion channels
- G protein-coupled receptors
- kinase-linked receptors
- nuclear receptors
How do ligand-gated ion channels work?
substance binds to it and opens the channel, allowing movement of channel-specific ions
What is an example of a ligand-gated ion channel?
acetylcholine and nicotinic receptors
What is the function of kinase?
an enzyme and second messenger that uses ATP to add a phosphate to targets, activating them
How do kinase-linked receptors work?
the receptor is on the cell membrane as two halves and binding bring them together, which activates kinase activity and causes a cascade
What is an example of a kinase-linked receptor?
epidermal growth factor receptor and lung cancer -> EGFR promotes cell growth, so patients with more of these proteins experience mroe growth
How do G protein-coupled receptors work?
they are receptors with 7 transmembrane domains coupled to a g protein and ligand binding activates the G protein which interacts with an effector
What is an example of G protein-coupled receptors?
muscarinic receptors and smooth muscle contraction
How do nuclear receptors work?
the receptor is NOT on the cell membrane, but in the cytoplasm -> ligand-receptor pair allows it to change conformation and it can move into nucleus where it binds to DNA and acts on gene expression
What is an example of nuclear receptors?
oestrogen receptor and breast cancer
Which 2 factors determine a receptor response?
affinity and efficacy
define affinity
how well a drug binds to a receptor
define efficacy
how well a drug activates a receptor
How are receptor responses measured?
concentration-response curves
How are concentration-response curves plotted?
a chosen response is recorded e.g muscle contraction and the recorded response is plotted against LOG agonist concentration
describe and explain the concentration-response curve
- initial low concentration gives limited response as low receptor binding
- more agonist is added and there is more binding
- a plateau is reached as we either have full receptor occupancy or we have added all agonist and can’t get a higher biological response
define Emax
the maximum response produced by an agonist
define EC50
the concentration of agonist needed to give 50% of Emax
How can we compare agonist drugs in the same biological system?
compare the profile of their concentration-response curves, Emax and EC50 values
What does it mean if another agonist has a curve to the right?
it has a higher EC50, so a higher concentration of agonist is needed to give the same response, so the agonist is LESS POTENT that the other
What do different EC50 values indicate?
different potencies for the receptor
define partial agonist
an agonist that binds to a receptor but does not produce a FULL response - either poor efficacy or affinity
What does the concentration-response curve look like for a partial agonist?
it will have an Emax below a full agonist and different EC50
define inverse agonist
an agonist that reduces a biological response below basal levels
What does the concentration response-curve look like for an inverse agonist?
Emax is below basal level
What is an example of an inverse agonist drug?
drugs that reduce heart muscle contraction -> heart has basal level of activity without any agonist present
define biased agonism
when different agonists bind to the same effector but activate different second messengers and create a different reponse
What is an example of biased agonism?
G protein-coupled receptors can signal through a G protein or arrestin
define arrestin
proteins that regulate the signalling of G protein-coupled receptors
define balanced agonist
an agonist that activates both pathways to the same level
What are the 2 types of competitive antagonist?
reversible or irreversible
define competitive antagonist
an antagonist competes with agonists for the same receptor binding site
How do reversible antagonists work?
increasing agonist concentration can outcompete antagonist
How do irreversible antagonists work?
they permanently bind to receptors, so no amount of agonist can dislodge it
How do reversible antagonists affect concentration-response curves of an agonist?
curve to the right but still can reach Emax, as a higher concentration of agonist A is needed to give the same response
How do reversible antagonists affect Emax and EC50?
Emax of the agonist stays the same, but EC50 of agonist increases
How do irreversible antagonists affect concentration-response curves of an agonist?
curve will be lower and to the right
How does an irreversible antagonist affect Emax and EC50 of an agonist?
Emax of agonist decreases, EC50 of agonist increase
How do we measure antagonism?
using the Schild plot and PA2
define Schild plot
a way to determine the nature and potency of an antagonist
What are the axes on a Schild plot?
X axis -> log (concentration of antagonist)
Y axis -> log (dose ratio -1)
What is the equation for dose ratio?
EC50 of agonist with antagonist / EC50 of agonist without antagonist
How do you determine the pA2 value?
pA2 vaule is where the line on the Schild plot intersects the X-axis (remember it is negative log of concentration)
What does pA2 measure?
antagonist potency
What is the pA2 equation?
pA2 = log(dose ratio -1) - log[antagonist]
What does a higher pA2 value indicate?
a more potent antagonist
What is indicated if two antagonists give the same pA2 value?
they act through the same receptor
Where do agonists and competitive antagonists bind on a receptor?
the orthosteric site
What is the allosteric site and its function?
another site on the receptor -> other molecules can bind here and modify the effects of an agonist
define affinity modulation
the process of altering how well the agonist binds to the orthosteric site
define efficacy modulation
the process of altering how well the agonist activates the receptor
define affinity allosteric modulator
a ligand that binds to a receptor and alters how well the AGONIST binds to the receptor at the orthosteric site
What do positive affinity allosteric modulators do?
increase how well an agonist binds to the orthosteric site, and decreases the concentration needed for the same reponse
What do negative affinity allosteric modulators do?
decrease how well an agonist binds to the orthosteric site, and increase concentration needed for the same response
define efficacy allosteric modulator
a ligand that binds to a receptor and alters how well the agonist activates the receptor -> the full response of the agonist will be increased or decreased
define allosteric agonist
an allosteric ligand that binds to a receptor and can cause a response on its own without need for an agonist
What type of cells are neurones?
postmitotic
define postmitotic
cells that are fully differentiated and unable to divide
define soma
the cell body of a neurone, an expanded area of cytoplasm where nucleus and organelles are found
Which organelle do neurones NOT have?
centrioles -> important in cell division, so don’t need them
What is the structure and function of the myelin sheath?
made up of Schwann cells and they insulate the axon
What are the 4 shape classes of neurones?
multipolar, bipolar, unpolar, anaxonic
What are the 3 classes of neurones?
afferent, efferent, interneurone
define afferent neurone
transmits signal from receptors to CNS
define efferent neurone
transmits signal from CNS to effectors
define interneurone
transmits signal from afferent to efferent neurones
What is a resting membrane potential (RMP)?
an electrical charge across the plasma membrane, with the interior of the cells negative compared to exterior
define chemical gradient
gradient based on concentration
define electrical gradient
gradient based on charge
What are the 2 types of movement across the plasma membrane involving proteins?
facilitated diffusion and active transporters (pumps)
define facilitated diffusion
when ions diffuse down their concentration gradient and the channels are selectively permeable to different ions
define active transport
when pumps move ions against their concentration gradient and create a concentration gradient across the membrane
How do Na+ and K+ pumps maintain excitability?
active transporters exchange 2K+ in for every 3NA+ out
What is the resting membrane potential in most neurones?
-70mV
Which equation is used to calculate the equilibrium potential for an ion?
the Nernst equation
give the Nernst equation
E ion = RT / zF x log [ion]outside / [ion]inside
Which other equation is used to calculate the resting membrane potential?
Goldman equation
define action potential
a brief change in the voltage across a membrane due to the flow of ions into and out of the neurone
What does the ‘all or nothing law’ describe?
if a stimulus is strong enough, an action potential occurs, which is always a full response i.e. can’t be strong or weak
What are the 5 phases of action potentials?
- hypopolarisation
- depolarisation
- overshoot
- repolarisation
- hyperpolarisation/undershoot
define hypOpolarisation
the initial increase of the membrane potential to the value of threshold potential
define depolarisation
the potential moving from the RMP to less negative values
define overshoot
the peak of the action potential being reached at about +40mV
define repolarisation
the potential moving back to the RMP (-70mV)
define hyperpolarisation/undershoot
the potential moves away from the RMP in a MORE negative direction, but the RMP is eventually restored due to K leak channel and sodium-potassium pump
action potential stage 1
membrane is at resting potential and VGNC and VGKCs remain closed
action potential stage 2
a stimulus causes depolarisation the threshold potential and VGNCs open
action potential stage 3
Na+ ions flow in and the membrane rapidly depolarises and more VG sodium ion channels open but VGKCs remain closed
action potential stage 4
VG sodium ion channels are inactivated and Na+ entry slows
action potential stage 5
VGKCs open and K+ begin to flow out, beginning repolarisation
action potential stage 6
VGNC channels fully close and VGKC remain open to give delayed hyperpolarisation -> eventually resting potential is restored
What are the properties of VGNCs?
- open rapidly with depolarisation at around -55mV
- moving away from -55mV causes inactivation
- inactivated channels are blocked during continued depolarisation
- inactivated channels move to a closed state during repolarisation
What are the properties of VGKCs?
- K+ channels slowly open during depolarisation at about +30mV
- they close slowly on repolarisation
What are the 2 classes of refractory period?
absolute refractory period, relative refractory period
What happens during the absolute refractory period?
action potentials cannot be generated as VGNCs are inactivated and can’t be activated again until the membrane is repolarised and resting state is restored
When does the refractory period occur?
from the start of an action potential to the point that voltage first returns to RMP
What happens during the relative refractory period?
the membrane potential is hyperpolarised by VGKCs and action potentials CAN be generated if the stimulus is strong enough to overcome hyperpolarisation and reach threshold
What is action potential propagation?
the process by which an action potential travels across a neurone
How does action potential propagation work (local currents)?
- stimulation at point A exceeds threshold
- local currents spread along axon and exceed threshold
- this opens VGNC and generate AP at point B
- VGNC inactivation occurs and open VGKC prevent back-propagation
What 2 factors does the velocity of action potential propagation depend on?
- axon diameter
- myelination
How does axon diameter affect action potential propagation velocity?
the larger the diameter, the faster the propagation as there is more space for ions to travel
define saltatory conduction
the propagation of action potentials along myelinated axons from one node of Ranvier to the next, increasing velocity
What causes Guillain-Barre syndrome?
the destruction of Schwann cells in the peripheral nervous system
What causes multiple sclerosis (MS)?
a loss of oligodendrocytes in the brain and spinal column
What are the 2 types of graded potential?
excitatory and inhibitory
What do inhibitory graded potentials do?
take the membrane further away from the threshold potential
What are the 4 types of excitatory graded potentials?
- temporal summation
- spatial summation
- no summation
- spatial summation of EPSPs and IPSPs
define temporal summation
2 excitatory stimuli close in time causes EPSPs to add together
define spatial summation
2 simultaneous stimuli at different locations cause EPSPs to add together
define no summation
2 stimuli separated in time cause EPSPs that do NOT add together
define spatial summation of EPSPs and IPSPs
changes in membrane potential that cancel each other out
define synapse
the point at which an electrical signal moves from one nerve cell to another
What are the 2 types of synapse?
electrical and chemical
What is the structure of an electrical synapse?
the pre and post-synaptic neurones are directly connected by gap junctions
What is the structure of an chemical synapse?
the pre and post-synaptic neurones are physically separated by the synaptic cleft and chemical transmitter from pre-synaptic neurone binds to receptors on post-synaptic neurone
What are gap junctions?
channels formed by connexons in both cell membranes and allow direct passage of ions and small molecules through the channels
What are the features of chemical synapses?
- synaptic vesicles filled with neurotransmitter on the inside of the presynaptic neurone
- voltage-gated calcium ion channels in presynaptic neurone
- neurotransmitter receptors on postsynaptic neurone
What are the 3 types of synapse in the CNS?
axo-dendritic, axo-somatic, axo-axonal
define axo-dendritic synapse
an axon synapsing onto a dendrite
define axo-somatic synapse
an axon synapsing onto a cell body
define axo-axonal synapse
an axon synapsing onto another axon or axon terminal
define neurotransmitter
a chemical messenger that is released from a pre-synaptic neurone
What are the sequence of events involved at a chemical synapse?
- neurotransmitter is synthesised and stored in vesicles
- AP arrives at presynaptic terminal
- AP depolarises the terminal and VGCC opem
- Ca2+ enter and trigger exocytosis
- transmitter diffuses down synaptic cleft and binds to receptors
- ion flow causes postsynaptic response
- transmitter is removed by enzyme breakdown or reuptake
- the vesicle is retrieved from the terminal membrane
What are the 4 key criteria for a substance being a neurotransmitter?
- substance must be present within the presynaptic neurone
- substance must be released in response to presynaptic depolarisation by an AP
- specific receptors for the substance must be present on the postsynaptic cell
- there must be a mechanism for removal and/or breakdown
What are the 2 types of neurotransmitter receptor?
ionitropic receptor, metabotropic receptor
What is an ionotropic receptor?
a ligand (transmitter) gated ion channel that opens to allow passage of ions through membrane in response to binding
What is a metabotropic receptor?
a g protein-coupled receptors -> binding activates g-protein which activates second messenger which can directly affect ion channels on membrane
What is a neuromuscular junction?
the synapse between a motor neurone and skeletal muscle
What is a neuromuscular junction also known as?
a motor endplate
Which neurotransmitter and receptor are used at neuromuscular junctions?
acetylcholine and nicotinic receptors
What type of receptor in the nicotinic acetylcholine receptor?
ionotropic or neurotransmitter-gated ion channel
How is acetylcholine synthesised?
in the presynaptic terminals by the enzyme choline acetyltransferase
How is acetylcholine broken down?
by acetylcholinesterase into acetate and choline
What is the main excitatory transmitter in the CNS?
glutamate
What type of receptor does glutamate activate?
both ionotropic and metabotropic receptors
What is the main inhibitory transmitter in the CNS?
GABA (G-aminobutyric acid)
What type of receptor does GABA work on?
a small family of ionotropic and metabotropic receptors
What type of potential does glutamate generate?
an excitatory postsynaptic potential (EPSP)
What type of potential does GABA generate?
an inhibitory postsynaptic potential (IPSP)
What do IPSPs do?
make a neurone less likely to generate an action potential
define gastrointestinal system
a network of organs and specialised cells that enable you to transform food into the energy and nutrients required for life
Which organs is the GI tract made up of?
mouth, oesophagus, stomach, small intestine, large intestine, anus
Name the accessory organs
salivary glands, liver, gallbladder, pancreas
define accessory organ
an organ that plays a role in the function of the GI tract but is not part of it
define mesentery
a membranous tissue that surrounds the organs of the GI tract
What is the function of the mesentery?
- holds intestines in place
- has lots of blood vessels and lymphatics for absorption and immunity
What prevents food travelling to the lungs?
the pharynx and epiglottis
What is the function of the oesophagus?
to transport food bolus to the stomach
What are the main functions of the stomach?
- mix food
- digest protein
- emulsify fat
How many layers is the stomach wall made up of?
4
Which cells is the stomach acid produced by?
parietal cells
Which 3 sections is the small intestine divided into?
duodenum, jejunum, ileum
What is the function of the small intestine?
primary site of absorption
What increases the surface area of the small intestine?
finger-like projections called villi that contain microvilli with epithelial cells on surface
Which 3 sections is the small intestine divided into?
ascending colon, transverse colon, descending colon
What is the function of the large intestine?
- role in conservation of water and ions
- storage of faecal matter
- crypts that are involved in lysosome secretion
How many sets of salivary glands do humans have?
3
What is the function of saliva?
- contains some digestive enzymes
- lubricates food with mucus
What is the function of the liver in digestion?
- produces bile and involved in excretion
- bile is needed for emulsification of fats
What is the function of the gallbladder?
- collects secretions from liver
- delivers bile to duodenum
What is the function of the pancreas?
- makes enzymes to digest proteins, fats, carbohydrates
- produces insulin and glucagon from islets of Langerhans
What are the 4 functions of the GI system?
- ingestion
- secretion
- movement
- digestion
define ingestion
the process of taking in food or drink through the mouth
define secretion
the release of substances that contribute to digestion
What are the 2 main types of movement in the GI system?
segmentation and peristalsis
define segmentation
‘squishing’ of substances backwards and forwards to help move them
define peristalsis
coordinated movement with contraction and relaxation of intestine
define digestion
breakdown of food into smaller components that can be absorbed into the bloodstream
What are the 2 types of digestion?
mechanical and chemical
define absorption
the process through which nutrients, water and electrolytes enter the blood (through villi and microvilli)
define excretion
the process by which metabolic waste is eliminated from the body
Which 2 main parts is the nervous system divided into?
the central and peripheral nervous systems
What is the central nervous system made up of?
the brain and spinal cord
define periphery
the area that is away from the centre of the body
define afferent neurone
a neurone that transmits an action potential from the periphery to the CNS
define efferent neurone
a neurone that transmits an action potential from the CNS to the periphery
define vertebrae
a stack of bones that surround the spinal cord
What are the 4 sections of spinal nerves that receive inputs and send outputs?
cervical, thoracic, lumbar, sacral
How do sensory inputs enter the CNS?
through the dorsal root into the spinal cord
What is the dorsal root ganglion?
where the cell bodies of axons are just outside the vertebrae in the spinal cord
What type of neurone are most sensory neurones?
unipolar -> have a cell body and one long axon
What is the simplest example of a connection between sensory neurone input and output back to the periphery?
the monosynaptic reflex
define monosynaptic
there is ONE synapse between the presynaptic and postsynaptic neurone
What type of neurone are most motor neurones?
multipolar
define reflex
when input is received by the periphery and the body provides output back to the periphery without any conscious thought
What do proprioceptors do?
sense position and movement
How does the knee jerk reflex work?
- tap the tendon attached to the quadriceps
- the tendon gets pulled, which stretches the quadriceps
- this is sensed by the muscle spindle fibres (proprioceptors)
- generates action potential
- action potential goes through dorsal root to spinal cord
- neurotransmitter is released in spinal cord
- this causes an action potential in a motor neurone, which causes the quadriceps to contract
What is the pathway of a reflex arc?
- receptor gives input to integrative centre
- integrative centre gives output to effector
What is USUALLY the integrative centre?
the spinal cord
How do sensory neurones vary?
by thickness and myelination
What does the extent of myelination determine?
the speed of an action potential
define ascending pathway
neuronal input travelling from the spinal cord to the brain
give an example of an ascending pathway in proprioception
- action potential comes into dorsal root
- goes up the spinal cord to a synapse at the brain stem (medulla)
- action potential crosses to the other side of the body
- it reaches another synapse in the middle of the brain called the thalamus
- eventually reaches the somatosensory cortex
define descending pathway
information going from the brain to the spinal cord
Where does all input from the periphery to the CNS BELOW the neck go to?
the spinal cord
Where does all input from the periphery to the CNS go to if ABOVE the neck?
the cranial nerves
define glial cell
a cell that is specialised to help neurones function but are NOT neurones
What are 2 examples of glial cells?
oligodendrocytes and astrocytes
What do oligodendrocytes do?
produce myelin -> there are different glial cells that do this in the peripheral nervous system called Schwann cells
What does astrocytes do?
act as a buffer to equalise concentrations of k+ ions -> there may be high concentrations of K+ ions if axons are generating many action potentials, so astrocytes ‘suck them up’ and move them to other parts of the brain
define the meninges
the 3 layers of membranes that cover and protect the brain and spinal cord
What is the outer membrane called?
dura mater
What is the inner membrane called?
the pia mater
What is the space between the inner and outer membranes called?
the sub arachnoid space
What is the sub arachnoid space filled with?
cerebrospinal fluid
What is the function of the choroid plexus?
it is a gland in the middle of the brain that produces cerebrospinal fluid
What does the cerebrospinal fluid contain?
salt and sugar -> high concentrations of Na+ and low K+ -> glucose and oxygen
What is the blood-brain barrier?
a semipermeable membrane separating the blood from the cerebrospinal fluid and brain
What is the structure of the blood-brain barrier?
tight junctions between the endothelial cells and blood vessel wall (tight junction is a seal between two cells that prevents leakage of content)
What does the blood-brain barrier do?
prevents substances leaking out of the blood vessels into the brain, including blood borne viruses and bacteria
Which cells acts as immune cells in the brain?
microglia
What are the 3 main characteristics of skeletal muscle?
- made up of fibres
- mutlinucleate
- attached to bone
- controls posture and movement
- voluntary control
- antagonistic sets of muscle
How do the multi-nucleate muscle cells form?
fusion of muscle cells during embryonic growth
define tendon
bundles of collagen fibres that attach muscle to bone
define myofibril
bundles of actin and myosin filaments that make up muscle cells
What is the main function of the sarcoplasmic reticulum?
stores calcium in vesciles which is important to release Ca2+ ions in response to signals from the nervous system
What are the 5 main components of sarcomeres?
- thin filaments
- thick filaments
- z-lines
- H zone
- M-line/discs
What are the thin filaments composed of?
actin, troponin and tropomyosin
Which band do the thin filaments make up?
the I band
What are the thick filaments composed of?
myosin and titin
What is the function of titin?
to act as a scaffold for the sarcomere
Which band do the thick filaments make up?
the A band
What are the Z-lines?
a network of proteins that hold the thin filaments (actin) in place and together
What are the Z-lines composed of?
alpha-actinin
What is the H zone?
a light area in the centre of the A band of a sarcomere that contains only thick filaments and NOT thin actin filaments
What are M-lines/discs?
proteins that link the central regions of the thick filaments
What is the M-line composed of?
myomesin
What is the structure of each myosin molecule?
- has a light and heavy chain that are intertwined
- has a double globular head
- half the head is facing the left, and half to the right
- the area between the double head is known as the M-region
What is the structure of each actin subunit?
- each subunit has an active site than can bind to the head of a myosin molecule
- tropomyosin is wound around eahc subunit
- tropomyosin is held in place by the calcium-binding protein troponin
How do the Z-lines work?
the alpha-actinins bind and cross-link the ends of F-actin filaments from adjacent sarcomeres at the Z line
What is the interaction between actin and myosin filaments regulated by?
troponin
How many types of troponin are there? What are they?
- Troponin I -> inhibitory
- Tropnin C -> calcium binding
- Troponin T -> tropomyosin binding
What happens when calcium binds to troponin C?
causes a conformational change that moves tropomyosin aside to expose the actin binding site that binds to the myosin head
What are the 3 main steps of skeletal muscle contraction?
- resting muscle state
- activation of contraction
- breaking the cross-bridge
What are the steps of the resting muscle state?
- energised myosin is bound to ADP and Pi
- tropomyosin covers the myosin binding sites on the actin filaments and prevents interaction
What are the steps of activating contraction?
- muscle stimulated by action potentials and cytosolic calcium levels increase
- calcium binds to troponin and moves it aside exposing myosin binding sites on actin
- the energised myosin molecule and ADP bind to actin
- the cross-bridge formation causes the release of ADP and Pi and movement of the crossbridge to cause contraction
What are the steps of breaking the cross-bridge?
- ATP binds to myosin and breaks the cross-bridge
- ATP is converted to ADP and myosin returns to its energised position
define motor end plate
the region of the muscle fibre directly under the terminal portion of the axon of the neurone at the neuromuscular junction
Which two components make up the neuromuscular junction?
the motor end plate + axon terminal
How does an action potential stimulate a muscle?
- action potentials in the motor neurone depolarise the axon terminal
- this opens voltage-gated calcium ion channels
- Ca2+ ions enter the cell and trigger release of acetylcholine from vesicles
- Ach diffuses and activates nicotinic acetylcholine receptors
- this causes depolarisation of the motor end plate causing an endplate potential
What are the steps of calcium release from the sarcoplasmic reticulum?
- an action potential in the muscle is propagated
- Ca2+ is released from the lateral sac
- Ca2+ binding to troponin removes the blocking action of tropomyosin
- the cross-bridge moves
- Ca2+ is taken up
- Ca2+ removal from troponin restores tropomyosin’s blocking action
What are the 2 main types of skeletal muscle fibres?
fast twitch fibres and slow twitch fibres
What are the features of fast twitch fibres?
- contract rapidly
- get energy from glycolysis
- anaerobic
- used for explosive power such as sprinting and powerlifting
What are the features of slow twitch fibres?
- contract slower
- get energy aerobically
- used for long periods of activity such as long-distance running
- fatigue resistant
How does genetic variation affect athletic performance for some?
- alpha-actinin 3 is expressed in a subset of fast twitch muscles
- a genetic variant encodes an early stop codon and causes a truncated form of alpha-actinin 3
- causes high performance in long distance running
What are features of cardiac muscle cells?
- single, polyploid nucleus
- striated pattern
- cells electrically connected by intercalated discs
- cells have 2 types of electrical activity -> pacemarker and cardaic action potentials
- heart rate is regulated by catecholamines
What causes the nucleus in cardiac cells to be polyploid?
nucleus has undergone extra DNA replication without the cell dividing
Where are the intercalated discs located?
the Z-line of the sarcomeres that hold the actin filaments together
What are the 3 types of intercalated discs?
- interdigitating folds
- mechanical junctions
- electrical junctions
define interdigitating fold
infolds at the end of cardiac cells that increase the surface area of cell-cell connection
What are the 2 types of mechanical junctions in cardiac cells?
Adherens junctions and desmosomes
What do Adherens junctions do?
join the cell membrane to the actin filaments of the cardiomyocytes to help the transmission of contractile force between different cells
What do desmosomes do?
give strong structural support between cardiomyocytes to ensure they can withstand the contractile forces
What are the electrical junctions in cardiac muscle called?
gap junctions
What is the function of gap junctions?
they allow the transmission of ions between cells allowing depolarisation
What are gap junctions made of?
a hexamer composed of connexins provided by each cell –> hexamers are shared between cells to form a gap junction with 12 subunits connecting the cells
Are cardiac pacemaker cells initiated by nerve stimulation?
no, but can be modified by stimuli from the autonomic nervous system
How do pacemaker cells generate cardiac action potentials?
they generate their own spontaneous ones
Where are the primary pacemaker cells?
in the sinoatrial node (SAN)
What are the steps of generating a pacemaker action potential?
- phase 4: a channel called the funny channel opens and allows influx of Na+ ions, causing a GRADUAL increase in membrane potential
- phase 0: T-type calcium ion channels open and allow influx, causing a rapid depolarisation of the membrane
- phase 1: voltage-gated K+ channels open and cause rapid repolarisation and K+ ions leave the cell
- the cycle repeats
What are the steps of generating cardiac muscle cell action potentials?
Phase 4: cells at resting potential known as diastole
Phase 0: voltage-gated Na+ ion channels open due to arrival of action potential from the neighbouring cell, allowing rapid influx of Na+ ions, causing rapid depolarisation
Phase 1: rapid inactivation of Na+ channels and opening and closing of K+ channels causes a very brief efflux of K+ ions as they leave, causing a ‘notch’ on the graph
Phase 2: plateau as the membrane potential remains relatively constant as the membrane is slowly repolarising
L-type Ca2+ channels allow Ca2+ ions to enter the cell after they are activated by sodium influx in phase 0
Phase 3: rapid repolarisation as L-type Ca2+ ion channels close and voltage-gated K+ channels open
Which factors increase heart rate from the SA node?
increased plasma adrenaline, increased sympathetic nerve activity
Which factors cause a decrease in heart rate from the SA node?
increase in parasympathetic nerve activity
How does Ca2+ release during the cardiac action potential cause more Ca2+ release? (calcium induced calcium release)
- L-type calcium channels open during the cardiac action potential
- small amounts of Ca2+ enter the cell to trigger the opening of Ryanodine Receptor calcium channels in the sarcoplasmic reticulum
- Ca2+ is released from the sarcoplasmic reticulum and binds to troponin to trigger cross bridge cycling
- Ca2+ is returned back into the sarcoplasmic reticulum by the sarco/endoplasmic reticulum calcium ATPase (SERCA)
- Na+/Ca2+ exchanger removes calcium out of the cell
- the membrane is repolarised by potassium channels at the end of the action potential
How is a myocardial infarction detected?
cardiac troponins are fragmented and released into the blood when the heart muscle is damaged
What is dilated cardiomyopathy (DCM)?
a heart condition caused by the left ventricle dilating, making it harder to pump blood around
What is DCM caused by?
mutations in genes including those encoding actin, myosin, alpha-actinin, titin or troponin
What are symptoms of DCM?
shortness of breath and fatigue as the left ventricle fails
What are the differences between skeletal msucle and smooth muscle?
- smooth muscle cells are much smaller than skeletal muscle cells
- less organised actin-myosin arrangement
- contraction is regulated by calcium binding to calmodulin, NOT troponin
Where is smooth muscle found?
tubular and hollow organs such as the airways, arteries, veins, intestines, uterus etc
What does relaxation of vascular smooth muscle cause?
vasodilation, increasing blood supply to the tissues
What does contraction of vascular smooth muscle cause?
vasoconstriction, decreasing blood supply to the tissues
What is the structure of smooth muscle in the intestine?
longitudinal and circular layer
Which layer of the stomach is made up of smooth muscle?
muscularis externa
What is the structure of smooth muscle in the stomach?
3 layers:
- inner oblique layer churns food and is responsible for mechanical digestion
- circular layer form the pyloric sphincter and controls flow of stomach contents into the duodenum
- longitudinal layer moves food towards the pylorus
What are the POSSIBLE functions of smooth muscle in the trachea and bronchia?
- peristalsis for expiration
- even distribution of airflow during ventilation
- supporting airway wall
- enhancing coughing
What are the 2 types of smooth muscle?
single unit and multi unit
What are the features of single unit smooth muscle?
- made of fibres in sheets
- cells connected by gap junctions
- muscle contracts as a syncytium
What are the features of multi unit smooth muscle?
- cells act as individual units
- few or no gap junctions
- allows fine grain control
What does smooth muscle have instead of Z-lines?
dense bodies
What do dense bodies do?
hold actin thin filaments allowing them to exert force -> they are attached to the sarcolemma by intermediate filaments
What are the 2 sources of calcium ions for smooth muscle contraction?
internal calcium stores and external influx through calcium ion channels
What is the calcium binding protein in smooth muscle?
calmodulin
What are the 3 major steps of smooth muscle contraction?
- resting muscle state
- activation of contraction
- breaking the cross bridge
What are the steps of the resting muscle state?
- the dephosphorylated myosin head group is held close to the myosin filament
What are the steps of activating contraction?
- the muscle is stimulated by neurotransmitters and cytosolic calcium levels increase
- calcium binds to calmodulin
- calcium-calmodulin complex binds to myosin light chain kinase (MLCK)
- MLCK is activated
- active MLCK uses ATP to phosphorylate the myosin light chains in the myosin head group
- this causes to cross bridge to move away from the thick filament to a position where it can bind to actin
What are the steps of breaking the cross-bridge?
- myosin is dephophorylated by myosin light chain phosphatase
- when Ca2+ levels are high, activity of MLCK is greater than MLCP activity, so myosin gets phosphorylated
- now Ca2+ levels have decreased, so MLCP activity is greater than MLCK, so myosin is dephosphorylated
How is the sarcoplasmic reticulum a source of calcium ions?
- action potentials can release Ca2+ stores from the SR near the plasma membrane
- second messengers can release Ca2+ stores from the SR
How does the muscle cell get Ca2+ from extracellular sources?
influx through voltage-gated Ca2+ channels in the plasma membrane
How is smooth muscle contraction in the GI tract initiated?
- slow waves are generated by pacemaker cells called interstitial cells of Cajal
- slow waves spread to the surrounding smooth muscle cells via gap junctions
How is contraction of smooth muscle through neurones stimulated?
varicosities release neurotransmitters that cause smooth muscle cells to contract or relax
define varicosity
an axon-like swelling of autonomic neurones that form motor units in smooth muscle
What are the differences between acetylcholine receptors in skeletal muscle compared to smooth muscle?
skeletal muscle= the nicotinic receptor activated by acetylcholine is an ion channel receptor
smooth muscle= the muscarinic receptor activated by acetylcholine is a G protein-coupled receptor
What are the steps of releasing internal Ca2+ stores after GPCR activation?
- trimeric G-protein with alpha, beta and gamma subunits
- activation of the GPCR activates the alpha subunit of the G protein by GDP/GTP exchange
- this causes dissociation of the alpha subunit bound to GTP from the beta-gamma subunit
- the GTP bound alpha subunit activates phospholipase C
- phospholipase C cleaves PIP2 into IP3 and DAG
- IP3 binds to IP3 receptors in the sarcoplasmic reticulum and opens calcium ion channels
- Ca2+ ions are released from the sarcoplasmic reticukum
What are the 2 main receptors in smooth muscle?
alpha-1 adrenergic receptor and beta-adrenergic receptor
What does alpha-1 adrenergic receptor do?
mediate constriction in most vascular smooth muscle
What does beta-adrenergic receptor do in smooth muscle?
mediate dilation of vascular smooth muscle and lung airway smooth muscle
How is asthma and COPD commonly treated?
- M3 muscarinic receptors control bronchioconstriction in the airways (hypersenstitive)
- beta-adrenergic receptors control smooth muscle relaxation and bronchiodilation
- beta-adrenergic agonists are used to treat asthma and COPD
define atherosclerosis
thickening or hardening of the arteries caused by a buildup of plaque in the inner lining of an artery
