Cellular neuroscience and physiology Flashcards
(149 cards)
1
Q
What are excitable cells? (examples, PD, key roles)
A
Examples of excitable cells: neurons, cardiac myocytes and skeletal muscle
Potential differnt (PD) across plasma membrane
Key roles in medical physiology and pathophysiology
2
Q
How does PD across membrane arise?
A
Passive movement
- Permeability of membrane
- Driving force (electrochemical gradient)
Active transport
- Against concentration and/or electrical gradient
- Requires expenditure of metanolic energy by the cell
3
Q
What can membranes be in relation to permeablility? (3)(model?)
A
Membranes can be:
Impermeable to an ion (no channels let ion through)
Slightly permeable to an ion (large driving force required)
Readily permeable (small driving force required)
*fluid mosaic model
4
Q
What are cell membranes like at rest?
A
Cell membranes at rest:
Fairly readily permeable to K+ and Cl-
Poorly permeable to Na+
Impermeable to various large organic anions
5
Q
Typical concentration of Na+, K+ and Cl- ECF and ICf?
A
Typical concentrations of Na+, K+ and Cl-
Sodium – lower ICF, higher ECF
Chloride – lower ICF, higher ECF
Potassium – higher ICF, lower ECF
Different species and cell types will have different approximate concentrations of ions.
6
Q
What is a concentration gradient? What is an electrical /potential gradient?
A
Concentration gradients – substances will move down a concentration gradient from an area of high concnetratoin through a permeable membrane to an area of low concentration.
Electrical (or potential) gradient – ions x- will move from an area of higher charge (+) to an area of lower charge (-) through a permeable membrane down an electrical gradient.
7
Q
What happens if both concentration and electrical gradients exist at the same time?
A
Need to convert concentration gradient into an equivalent electrical gradient
The nernst equation
Ex = - RT/ZXF Ln (x)i/(x)o
X = ion
Ex = equilibrium potential for x
R = universal gas constant
T = temperature
Z = the valence of the ion (eg +1 for K+, -1 for Cl-)
F = faradays constant
(x)o = concentration of x outside the cell
(x)i = concentration of x inside the cell
*this equation can be expressed without the minus sign if the concentrations are inverted
So at 37*c (body temperature) = Ex = 61 log (x)o / (x)i millivolts
8
Q
What is important to remember about the Nernst equation?
A
Tells us the magnitude of the electrical gradient that would exactly balance a given concentration gradient of a given ion
Gives us the equilibrium potential for that ion
9
Q
What 2 fundamental properties of cells give rise to the existence of a resting membrane potential?
A
Unequal distribution of ions across membrane (maintained by Na+/K+ pump)
Selective permeability of the cell membrane (Pk»_space; P Na)
10
Q
Limitation of Nernst equation? What is used instead?
A
There are lots of different ions which contribute to resting membrane potential and the nernst equation only considers single ions
The Goldman-Hodkin-Katz equation is used instead.
11
Q
What do changes in membrane potential determine? What are EPSPs? What are IPSPs?
A
Changes in membrane potential determine if an action potential will occur or not (all or none)
Excitatory neurotransmitters cause small changes in membrane potentials excitatory postsynaptic potentials (EPSPs) can sum and cause an action potential to occur
Inhibitory neurotransmitters cause inhibitory postsynaptic potentials (IPSPs) which can prevent action potentials firing
Action potentials are required for correct functioning of the brain, heart and skeletal muscles
12
Q
What is a ‘threshold’?
A
Degree of depolarisation that triggers action potential
Determined by the ion channels in a membrane
Varies between different neurons and different parts of the same neuron
Generally speaking: thicker fibres have lower thresholds (because their diameter provides less resistance to flow of ions)
13
Q
How do ligand gated ion channels work?
A
Neurotransmitter binds
Channel opens
Ions flow across membrane
14
Q
How do G-protein receptors work?
A
neurotranmitter binds
- G-protein is acitvated
- G-protein subunits or intracellular messengers modulate ion channels
- ion channels opens
-ions flow across membrane
15
Q
What is the ionic basis of rising phase and falling phase?
A
Rising phase = depolarisation caused by Na+ influx
Falling phase = repolarisation caused by K+ efflux
16
Q
What is the positive feedback cycle? Is Na+ or K+ channels faster?
A
Triggering event – depolarisation (decreased membrane potential) - opening of some voltage gated Na+ channels – influx of Na+ (which further decreases membrane potential)
Voltage gated potassium channels are comparatively slower to open and close than voltage gated sodium channels.
17
Q
What is the absolute refractory period?
A
The absolute refractory period is a brief timeframe during which a neuron or muscle cell cannot respond to another stimulus, no matter how strong, immediately after an action potential has been generated.
18
Q
What is the relative refractory period?
A
The relative refractory period is a phase following the absolute refractory period in an action potential where a second action potential can be initiated but requires a stronger stimulus than usual.
19
Q
What junctions do skeletal muscles have?
A
Skeletal muscle: neuromuscular junction
Thick, myelinated axons: rapid conduction (limbs 40-65m/s)
Excitation contraction coupling
Propagation of (action potential) AP down into T tubules (carving paths through a mountain analogy)
20
Q
What is the excitation contraction coupling process in skeletal muscle?
A
Propagation of AP into T-tubules
Activation of dihydropyridine receptors (DHPR)(t-tubules; conformational coupling with ryanodine receptors RyR)
Release of calcium from sarcoplasmic reticulum (SR)
Binding of Ca2+ to troponin (conformational change tropomyosin)
Cross bridge formation (actin and myosin; ATP)
Cross bridge cycling (power stroke; release of ADP + Pi)
Ca2+ removed from troponin restoring tropomyosin and Ca2+ taken back up by SR
21
Q
How is calcium released into the sarcoplasmic reticulum?
A
Activation of dihydropyridine receptors (DHPR)(coupling with ryanodine receptors RyR)
Release of calcium from sarcoplasmic reticulum
22
Q
What is the sliding filament theory?
A
Explains muscle contraction as a process where actin and myosin filaments within muscle cells slide past eachother, shortening the sarcomere and causing the muscle to contract. This sliding movement is driven by the interaction of myosin heads with actin filaments, powered by ATP hydrolysis.
23
Q
What are actin and myosin?
A
Actin and myosin -
Muscle cells contain thin actin filaments and thick myosin filaments, arranged in repeating units called sarcomeres
24
Q
What is calciums role in the sliding filament theory?
A
Calcium role -
The release of calcium ions triggers the movement of tropomyosin, revealing myosin binding sites on the actin filaments
25
What is the myosin-actin interaction?
Myosin heads bind to these exposed sites, forming cross bridges
26
What is a power stroke in the sliding filament theory?
Power stroke -
The myosin heads then pivot, pulling the actin filaments towards the centre of the sarcomere, a process called the power stroke
27
What is ATPs role in the sliding filament theory?
ATPs role -
ATP hydrolysis provides the energy for the myosin head to detach, reset and reattach further along the actin filament, repeating the cycle
28
What happens during relaxation in the sliding filament theory?
Relaxation -
When the nerve signal stops, calcium ions are pumped back into the sarcoplasmic reticulum, tropomyosin blocks the myosin binding sites and the muscle relaxes.
29
What are the 3 types of muscle tissue?
Cardiac (branched, straited, 1 nucleus, intercalated discs at ends of fibres which help organised contraction, involuntary)
Smooth (no-striations, spindle shaped with 1 nucleus, involuntary)
Skeletal (voluntary control, striated, long cylinders, multinucleated)
30
What are the 4 features of muscle?
Extensibility
Elasticity
Excitability
Contractility
31
What is an insertion point, origin point, agonist and antagonist?
Insertion point – attached to bone that will move
Origin point – attached to fixed part of bone
Agonist – main mover
Antagonist – helps keep position/does opposite
32
What are muscle fibres made up of?
Muscle fibres are made up of strips of myofibrils, which are made up of repeating elements called sarcomeres. (contributes to straited look)
33
What 4 components make up the sarcomere?
Actin (thin filaments, made of protein)
Myosin (thick filaments, made of protein)
Z-lines (where a sarcomere ends, where the thin filaments attach)
M line (where thick filaments attach)
34
What must happen for muscle contraction?
For muscle contraction, the sarcomere must shorten.
When the sarcomere contracts, the (actin) thin filaments will be pulled by (myosin) thick filaments towards the centre, so there is overlap and the z-lines will be moved closer together
35
How are cross-bridges formed? Powerstroke?
Myosin has structures called myosin heads (hundred of them), they are bound to ATP (hydrolysis results in ADP + Pi). The myosin head then binds to actin, forming a cross bridge.
The myosin head can then perform a power stroke, which releases ADP and phosphate, so actin filament slides towards centre. A new ATP molecule can bind to the myosin head, which causes detachment of myosin head from actin filament.
36
How does rigor mortis link to the sliding filament theory?
Rigor mortis – myosin heads fixed on actin filament, no longer creating ATP
37
How is sliding filaments regulated so muscle contraction isn't constant?
On actin, tropomyosin is (a regulatory protein) and blocks the binding sites.
Troponin complex (another regulatory protein) blocks myosin binding sites.
When neurons stimulate muscle, triggers release of calcium. Calcium binds to troponin, which has a conformational change, which moves the tropomyosin out of the way of the myosin binding sites.
38
What is cross-bridge cycling?
Actin and myosin dissociate when ATP is bound by myosin
ATP breakdown to ADP and Pi causes a change in the angle of the head region of the myosin molecules, this enables it to move relative to the thin filament
This cycle is then repeated. This process is known as cross-bridge cycling.
39
Why is sliding filament theory pathologically relevant?
Rigor mortis is caused by depletion of ATP
ATP causes actin-myosin bridges to separate during the relaxation of the muscle
Without ATP to separate the cross-bridging skeletal muscles are locked in place
As part of the decomposition process, myosin heads are eventually degraded by cellular enzymes allowing release of the cross-bridges and the muscles to relax
Peak rigor mortis – 13 hrs after death
Decomposition of myofilaments – 48/60 hrs after the peak of rigor mortis
40
How is muscle contraction ended?
Calcium is then pumped back into the SR to end muscle contraction
41
Summary of muscle contraction
Action potential propagates
Depolarisation of sarcolemma and t-tubules
Activation of DHP receptors and ryanodine receptors
Calcium release from terminal cisternae of sarcoplasmic reticulum (SR)
Contractile machinery activated
Calcium pumped back into SR (active process – requires ATP)
Cacium diffuses to terminal cisternae of SR ready to be released again
42
What experiment is used for length tension curve?
Experiments initially conducted on isolated frog muscle fibre
Clamp both ends and stretch the muscle fibre
Produces length tension curve for a single muscle fibre
*molecular cross-bridges are important for skeletal muscle tension
43
What is a myogram?
Mechanisms of single fibre contraction
MYOGRAM – measure twitch tension development in muscle
Latent or latency period
Contraction phase
Relaxation phase
7-100ms depending on muscle stimulated
44
How can skeletal muscles be classed?
A single contraction or twitch
Skeletal muscles are classified as being fast or slow twitch based on speeds of sarcomere shortening
45
What are the morphological differences between fast and slow twitch muscle fibres?
Morphological differences too:
Fast = white (lower myoglobin and capillary content)
Slow = red (high myoglobin and capillary content)
Time course of contraction is dependent on muscle fibre type (1, 2a or 2b)
46
What is tetanus?
Tetanus = the prolonged contraction of a muscle caused by rapidly repeated stimuli.
47
What is TFF? What are the 4 categories?
TFF = the frequency of action potentials that are needed to not see summation and produce a smooth graded contraction as seen in normal muscle contraction.
Single muscle twitches (5Hz) - complete relaxation of muscle
Temporal summation (10Hz) - muscle unable to completely relax – tension rises
Unfused tetanus (25 Hz) - muscle unable to completely relax – tension rises and falls
Fused tetanus - (50Hz) - smooth graded contraction. The relaxation phase is eliminated
48
What is the ultrastructure of cardiac tissue?
-10 um diameter
-100um in length
Intercalated disks separating the fibres
49
What are the mechanical and electrical junctions in cardiac tissue?
Mechanical junctions:
Fascia adherens
Desmosomes
Electrical junctions :
Gap junctions
50
What is a desmosome and what are gap junctions?
Desmosome = mechanical junctions between adjacent muscle fibres
Gap junctions = electrical conductivity between adjacent muscle fibres
51
What is the main function of cardiac muscle? (SAN)
Highly organised contraction
Pumps blood around cardiovascular systems
Action potential initiated in Sino-atrial Node (SAN) passes quickly through electrical syncytium – firing action potentials spontaneously
Refilling of heart requires synchronised relaxation
Abnormal activity can result in pathological conditions
52
What are the 2 types of cardiac action potentials?
2 types of cardiac action potentials:
Slow response (pacemaker cells)
Fast response (cardiac action potential)
53
What cells in the heart show different responses? (fast or slow)
Sinoatrial node (SAN) - slow
Atrial nad ventricular myocytes – fast
Purkinje fibres – fast
Atrioventricular node (AVN) - slow
54
What are the 4 phases for fast response cells or non-nodal cells?
Atrial and ventricular myocytes, Purkinje fibres
Stable resting membrane potential (RMP)
Phase 0 due to Na+ entry
Phase 1 initial repolarisation due to K+ efflux
Phase 2 due to Ca2+ entry (different in cardiac muscle) and sodium-calcium exchanger
Phase 3 more K+ efflux
Phase 4 RMP slightly more negative than RMP at the beginning
55
What are the 4 phases for slow or pacemaker cells?
Sinoatrial node (SAN), Atrioventricular node (AVN)
Unstable resting membrane potential (RMP) allows spontaneous depolarisation
No early repolarisation (phases 1 and 2) as in fast response cells
Phase 0 due to slow inward current of Na+ and Ca2+ influx causing depolarisation
Phases 1 and 2 are not present, as a result, phase 0 is followed by phase 3
Phase 3 repolarisation due to closing of calcium channels and efflux of K+
RMP (phase 4) is slightly less negative, gradual depolarisation
56
What is the relationship between action potential and contraction of cardiac muscle?
Contraction force follows the action potential due to excitation-contraction coupling
57
What are pacemaker slow response cells?
Significance of pacemaker potential (SAN)
Can fire an action potential without neuronal input due to unstable RMP
58
What is the ionic basis of pacemaker potential?
Funny channel (unusual behaviour: open at hyperpolarised potentials: inward Na+ current
Allowing positive charge in at rest causing unstable RMP
59
What happens in the heart during the absolute refractory period? (ARP)
The heart has to relax fully between beats
Important adaptation of cardiac muscle
Allows heart to relax fully in between beats
Inactivation of Na+ channels after approximately 1ms (reactivate at around –20mV)
Fibrillation can oocur if duration of ARP is decreased
60
What are the functions of thick and thin myofilaments?
Typical arrangement in skeletal and cardiac muscle
Striated appearance: alternating light (I bands) and dark (A bands)
Helps stabilize filaments during contraction
61
What are some of the important proteins in cardiac muscle?
Scaffolding proteins (meromyosin, C protein, nebulin and a-actinin)
Elastic protein ‘titin’ enabling relaxation: prevents overstretching and may also serve signalling role as a stretch sensor
62
What is the process of excitation contraction coupling in cardiac muscle?
Action potential enters through adjacent cell
Voltage gated Ca2+ channels open and Ca2+ enters the cell. The main soruce of Ca2+ is extracellular
Ca2+ induces Ca2+ release from SR (calcium induced calcium release)
Ca2+ ions binds to troponin enabling filament sliding
Muscle relaxes when Ca2+ unbinds from troponin
Ca2+ is pumped into SR for storage
Ca2+ is exchanged with Na+ at the sarcolemma
The NA+-K+ ATPase restores Na+ gradient
63
What differences are there in cardiac muscle to provide calcium?
DHPR and RyR are not conformationally coupled in cardiac muscle
Main source of Ca2+ is extracellular. There is some Ca2+ from SR but the main source is extracellular
NCX = sodium-calcium exchanger
T-tubules and sarcoplasmic reticulum (SR)
Extracellular ‘trigger’ Ca2+
Calcium induced calcium release (CICR). Ca2+ binds to ryanodine receptor (RyR) enabling it to release more Ca2+
64
What is the role of intracellular (Ca2+) in contraction and relaxation of cardiac muscle ?
Contraction
Calcium comes in through L-type calcium channels
Ryanodine receptors (RyR)
Relaxation
SERCA or SR pump (pumping Ca2+ back into the SR)
NCX (sodium calcium exchanger) 3Na+ - 1Ca2+
Sarcolemma Ca++ ATPase
65
Why does cardiac muscle have high stretch resistance?
Cardiac muscle (A) has a high resistance to stretch compared to skeletal muscle (B)
High abundance of connective tissue prevents muscle rupture and overstretching
66
What 3 things can be measured from a length tension curve?
RT = resting tension
TT = total tension
AT = active tension
67
What is Frank-starlings law?
Stretching occurs at times of increases venous return
Force of contraction is increased by stretch and enhanced by sympathetic stimulation
Important mechanism
Helps heart pump whatever volume of blood is receives
68
What is positive chronotropy, iontropy, lusitropy?
Positive chronotropy = increase rate of contraction
Positive iontropy = increase force of contraction
Positive lusitropy = increased rate of relaxation
69
Where is the location of smooth muscle?
Internal organs (viscera)
Walls of blood vessels
Around hollow organs (eg bladder)
Layers around respiratory, circulatory, digestive and reproductive tracts
70
What are the functions of smooth muscle?
* Move food, urine and reproductive tract secretions.
* Control diameter of respiratory passageways.
* Regulate diameter or blood vessels
71
What is the structure of smooth muscle?
Cells
* spindle-shaped
* Length ~ 100-300m
* Width ~ 2-5 m
* Single nucleus
Smooth muscle fibres
* often embedded in a matrix of connective tissue
* arranged in series and in parallel with one another
Not striated (compare this toskeletal and cardiac muscle)
72
What does it mean that smooth muscle are Innervated by efferent fibres of the autonomic nervous system (ANS) ?
Controlled by = innervated
Sympathetic/parasympathetic
Excitatory – contraction
Inhibitory – relaxation
Lack of voluntary control – autonomic reflexes
73
What are varicosities and what do they do?
Varicosities = pre-synaptic terminals
Presynaptic terminals (synaptic knobs)
Very close to effector cells (smooth muscle)
Release neurotransmitter
74
What is the process of excitation coupling in smooth muscle?
Hormones or neurotransmitters:
Open voltage or ligand gated Ca2+ chennels in the sarcolemma, causing Ca2+ influx
OR
Bind to G-protein coupled receptors and induce generation of IP3
Extracellular Ca2+ (main source) or IP3 induced Ca2+ release from SR
Ca2+ binds to calmodulin in the sarcoplasm
Ca2+-calmodulin complex activates myosin light chain kinase (MLCK)
Active MLCK phosphorylates MLC heads, enabling muscle contraction
Muscle relaxes as ca2+ is pumped into SR for storage
Ca2+ is also exchanged with Na+ at the sarcolemma
The Na+-K+ ATPase restores Na+ gradient
75
What is the difference between single unit and multiunit smooth muscle?
Single unit -
Gap junctions cause propagation and the whole muscle functions together to contract (gastrointestinal tract, bladder)
Multi unit -
Different parts of the muscle can function independently (iris, vasculature (artery lining), airways (trachea)
*if you are unsure whether a smooth muscle is single unit or multi unit, consider the function of smooth muscle
76
What is phasic and tonic contraction?
A phasic smooth muscle that is usually relaxed, example: esophagus
Relatively quick contraction with short durability (easily fatigued)
A tonic smooth muscle that is usually contracted, example a spincter that relaxes to allow material to pass
Relatively slow contraction with long durability (resistant to fatigue)
77
What is the relationship between membrane potential (Em) and generation of force (F) in different types of smooth muscle?
Action potentials lead to a twitch or larger summed mechanical responses. Characteristic of single unit smooth muscles
Rhythmic activity produced by slow waves that trigger action potentials. Burst of action potentials
78
What is subthreshold activity?
Tonic contractile activity related to membrane potential in the absence of action potentials
Pharmocomechanical coupling; changes in force produced by adding/removing drugs or hormones
*no significant effect on membrane potential
79
Sarcoplasmic reticulum and Ca2+ in smooth muscle
Ca2+ to allow contraction comes from SR and extracellular fluid (main source)
SR less well organised or developed in smooth muscle (compared to cardiac and skeletal muscle
SR is adjacent to cellular membrane and invaginations (these are called caveolae in smooth muscle)
80
What regulates smooth muscle contraction?
Smooth muscle contraction is thick filament regulated (myosin)
81
What is 'relaxed' state in smooth muscle?
Relaxed state: cross bridges present in high energy myosin-ADP-Pi state
Binding of myosin to actin depends on phosphorylation of the cross-bridge by Ca++-calmodulin dependent myosin light chain kinase (MLCK)
Cross bridges cycle until myosin is dephosphorylated by myosin phosphatase
Removal of Ca2+ from the cell promotes relaxation of smooth muscle
82
What is latch state of smooth muscle?
Latch state = an adaptation of smooth muscle which allows sustained muscle tone
83
What is the Hai and Murphy model (1988)?
Enables sustained smooth muscle tone with low rate of cross bridge cycling (so low rate of ATP usage)
Occurs when some of the cross-bridges attached to thin filaments become dephosphorylated (by myosin phosphatase)
This greatly slows rate of cross-bridge detachment therefore maintaining tone
Filaments tend to remain ‘locked’ together
84
What are the 4 different types of smooth muscle? Examples?
The same structural components but regulated in different ways to allow their different functions.
Normally contracted – spincters
Normally partially contracted (tone) - blood vessles,, airways
Phasically active – stomach, intestines
Normally relaxed- esophagus, urinary bladder
85
Similarities to skeletal and cardiac muscle?
Sliding filament theory and cross bridge cycling occurs (although regulation is different)
Calcium plays an important role in contraction
86
Differences (compared with skeletal and cardiac muscle)
Smooth muscle contraction is thick filament regulated
Contraction can be slow and sustained mainting muscle tone due to latch state
87
What are ion channels?
Selective
Conductance (measured in picosiemens pS)
The single channel conductance of typical ion channels ranges from 0.1 to 100pS
Gating = fluctuation between open and closed states
*trace of ions moving in and out of a cell when the ion channels are open and closed
88
Factors that control gating of ion channels?
Membrane voltage (eg depolarisation – excitable cells lecture)
Extracellular agonists or antagonists (eg ligand gated)
Intracellular messengers (eg Ca2+, ATP, cGMP)
Mechanical stretch of the plasma membrane (physical stimulation)
89
What is an inotropic receptor and example of this?
Activation of receptor causes a pore to open through which ions can pass
Examples include:
Ligand gated sodium channels (eg AChR nicotinic = nAChR, not muscarinic – these are GPCRs)
Voltage gated sodium channels (Nav1.4 in action potentials)
TRPV1 receptors (receptor for capsaicin in chilli)
90
What is an ionotropic receptor?
Fast acting
‘on’ or ‘off’ - all or none
Receptor is made up of multiple subunits
Example of function is in triggering an action potential
91
What are metabotropic receptors?
AKA g-protein receptors
- activation of receptor initiates an intracellular signalling mechanism (ions do not pass through the receptor protein)
Examples include:
Muscarinic AChRs = mAChR
Metabotropic glutamate receptors (mGluRs)
Adrenic receptors of the autonomic nervous system (eg beta-adrenergic receptors in heart)
Slower prolonged response compared to ionotropic receptors
Can amplify or dampen signals:
Gs = stimulatory
Gi = inhibitory
Receptor proteins are monomers.
92
What are the key features of membranes?
Hydrophobic core
Effective barrier to movement of virtually all biologically important solutes
Intracellular and extracellular fluids are primarily water (in which solutes such as ions, glucose and amino acids are dissolved)
Gases (eg O2 and CO2) and ethanol can diffuse across lipid bilayers
Movement of water and solutes is restricted
93
What are water channels? What can they regulate?
Membranes are not very permeable to water = channels
Water channels = aquaporins (AQPs)
Widely distributed throughout body, especially in kidney
Different isoforms found in different cell types
Amount of H2O influx/efflux can be regulated:
Altering number of AQPs in the membrane (membrane protein trafficking)
Changing their permeability (ie gating) eg by pH
94
What are the 3 major solute carrier functional groups?
3 major functional groups:
Uniporters (transport one substance)
Symporters (transport more than one substance in the same direction)
Antiporters (cotransports substance in different directions)
95
What are uniporters?
Transport a single molecule across membrane
Example GLUT2 (brings glucose into the cell)
Mutations can cause diabetes
96
What are symporters?
Couple the movement of 2 or more molecules/ions across the membrane
Molecules transported in the same direction (co-transport)
Example NKCC2 found in the kidneys
1Na+, 1K+ and 2Cl- symporter
Critically important for diluting and concentrating urine
97
What are anti porters?
Couple movements of two or more molecules/ions across the membrane in opposite directions
Also called ‘exchangers’ and ‘counter transporters’
Example: Na-H exchanger
Na+-H+ antiporter
Found in all cells
Important role in regulating intracellular pH
98
How does EC coupling in cardiac myocytes work?
EC coupling in cardiac myocytes
Prolonged action potential which propagates down T-tubules
Slow inward ca++ current through a voltage-gated L type Ca++ channel in the sarcolemma
Electrochemical coupling: small amount of Ca++ entry triggers Ca++ release from SR
(can initiate AP in absence of extracellular Ca++ but short duration and no contraction)
99
What are ATP dependent ion transporters?
Example: Na+, K+ATPase (also known as Na+K+ pump)
Found in all cells
Three subunits (alpha, beta, FXYD)
Alpha subunit has binding sites for Na+, K+ and Ouabain (inhibitory)
100
What is H+-ATPase?
Vacuolar H+-ATPase: found in membranes of many intracellular organelles (eg lysosomes)
Plasma membrane H+-ATPase: important role in urinary acidification
101
What are ABC transporters?
An example of ABC transporter – cystic fibrosis transmembrane regulator (CFTR)
102
What is primary active transport?
Transport is directly coupled to ATP hydrolysis (to move substances against their concentration gradient)
103
What is secondary active transport?
Energy for the transport comes from the electrochemical gradient. The energy from one molecule is used to move another molecule (s) against its electrochemicl gradient (eg 3Na+-Ca2+ antiporter)
104
What is 'diffusion'?
When a solute is added to a solvent, solute particles will move randomly (Brownian motion) from area of high concentration of solute particles to an area of low concentration of solute particles (down their concentration gradient) until equilibrium is reached
105
What is osmosis?
Diffusion of water across a semi permeable membrane
Membrane is freely permeable to water but not permeable to solute
Water diffuses from a high water concentration to low concentration (note high water concentration = low solute concentration)
106
What is hydrostatic pressure?
Hydrostatic pressure is the pressure exerted by a stationary fluid on an object: a pushing force
107
What is osmotic pressure?
The osmotic pressure of a solution is a measure of the tendency for water to move into that solution because of its relative concentration of non-penetrating solutes and water – a ‘pulling force’
108
When will net movement of water stop?
Net movement of water continues until the opposing hydrostatic pressure exactly counterbalances the osmotic pressure
109
What is interstitial fluid?
The fluid found in the spaces around cells
110
What is molarity?
Molarity
Number of molecules in a solution
Mol/L (remember units)
Moles = mass/mr
111
What is osmolarity?
Number of particles in a solution
Osm/L
112
Explain molarity and osmolarity in glucose and NaCl
Glucose
Molecules do not separate out in solution and therefore molarity and osmolarity are the same (molarity= 5.5mM/L, osmolarity = 5.5mOsm/L)
NaCl
Separates out into 2 different ions (na+ and cl-) therefore the osmolarity is double the molarity (molarity = 1Mol/L, osmolarity = 2 Osm/L)
113
What is tonicity? What are the 3 types of solution?
Tonicity
The effect the osmotic pressure gradient has on cell volume
Cells change shape due to net movement of water (into or out of cells)
Hypertonic solution, isotonic solution, hypotonic solution
114
What will happen to the water when a cell is placed in hypotonic, isotonic and hypertonic solutions?
Cell placed in hypotonic solution – water will enter the cell causing it to swell
Cell placed in an isotonic solution (isotonic=the 2 solutions have the same solute concentration) - no net water movement
Cell placed in a hypertonic solution – water will leave the cell, causing it to shrink
115
What is osmolality? How is different from osmolarity?
Osm per kg of body weight (osm/kg)
Useful for human/medical studies
Normally about the same as osmolarity
Normal plasma values 280-295mOsm/kg
So
Osmolarity = osmoles per volume
Osmolality = osmoles per weight (typically kg)
116
Why is osmolarity and osmolality clinically important?
Water is the major constituent of the human body (63% of adult male and 52% of adult female
Water moves between body compartments eg from intracellular fluid (ICF) to extracellular fluid (ECF= 75%, interstitial fluid +25% plasma)
Kidneys play important role in regulating fluid balance
Investigation of clinical problems eg dehydration, kidney function
117
What does it mean if extracellular fluid is hypotonic and hypertonic? How is this medically relevant?
Hypotonic (positive water balance): cells swell and then undergo regulatory volume decrease (RVD)
Hypertonic (negative water balance) cells shrink and then under regulatory volume increase (RVI)
Medically relevant
Can lead to abnormal brain function
Cause: dehydration
Cerebral edema
Other clinical relevance – changes to red blood cells
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What are the 2 components of the nervous system?
Central nervous system (CNS) = brain and spinal cord
Peripheral nervous system :
Somatic (eg motor nerves from CNS to skeletal muscles)
Autonomic (nerves from CNS to internal organs, eg heart, GI tract etc (can be subdivided again into parasympathetic and sympathetic
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What are the 2 parts of the peripheral nervous system and what do they do?
Peripheral nervous system
Somatic nervous system
Motor neurons to skeletal muscles
Voluntary control
Autonomic nervous system
Neurons to visceral organs (eg heart)
Involuntary conrol
Parasympathetic - ‘rest or digest’
Sympathetic - ‘flight or fight’
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What are the afferent and efferent neutrons?
Afferent – away from sensory
Efferent – effector organ
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What are synapses?
the small gap that exists between a pre and post synaptic membrane
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What are excitatory and inhibitory synapses?
Excitatory synpases – electrical activity in presynaptic neurone increase excitability of postsynpatic neurone (inhibitory synapses = decrease)
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What are the 2 types of synapses?
Chemical synapses – prevent direct electrical propagation of AP from pre-to post synpatic neuron
Electrical synapses exist but they are rare in the CNS but do exist
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What is chemical synaptic transmission?
Synaptic delay – 0.5ms
Synapse is 20-30mnm
Removal:
= enzymes
=reuptake
=uptake by glial cells
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How does vesicles fuse with pre-synaptic membrane? What are FPMs?
FPMs = fusion protein macromolecules
Opening of Ca2+ channels and actin
FPM separate and allow fusion
Vesicle membrane incorporated into presynaptic membrane
Clathrin molecules assist inward movement of the vesicle membrane. Dynamin assists in FPM pairs and pinching the neck of the emerging vesicle
Vesicle is now free for recycling
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What are the 3 key mechanisms by which neurotransmitters are removed from the synaptic cleft?
Enzymatic breakdown
Active reuptake (rapid)
Pumped back into pre-synaptic terminal
Active uptake (rapid)
Pumped into glial cells
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What are EPSPs and IPSPs?
EPSP = excitatory post-synaptic potential (increase potential)
IPSP = inhibitory post-synaptic potential (decrease potential)
A bit like mini action potentials which cause a small transient change in membrane potential of a cell
Upward deflection – decrease in potential
Downward deflection – increase in potential
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What are converging and diverging neurons?
Convergence – integrating information
Divergence – networkds and response
To fire or not to fire – summation of post-synaptic potentials
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What is presynaptic inhibition?
Inhibition before the synapse that you are recording at
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Why is presynaptic inhibition important?
Changes in membrane potential determine if an action potential will occur or not (all or none)
Excitatory neurotransmitters cause small changes in membrane potentials (EPSPs) which can sum and cause an action potential to occur
Inhibitory neurotransmitters cause IPSPs which can prevent action potentials from firing
Action potentials are required for correct functioning of the brain, heart and skeletal muscle, they are absolutely vital
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What is a neutron, nerve fibre, nerve, intracellular recording and extracellular recording?
Neuron – a single nerve cell
Nerve fibre – the axon of a single neuron
Nerve – a bundle of nerve fibres
Intracellular recording – recording electrical activity across a membrane of one single cell (one electrode is inside the cell and one is outside)
Extracellular recording – recording electrical activity from a population of cells (both electrodes are outside the cell)
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What are intracellular recordings?
Eg slices of brain tissue
Kept alive in a solution that mimics the extracellular fluid (cerebrospinal fluid, CSF)
Record action potentials/ synaptic communication using electrodes
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What does it mean that lipid membranes have capacitance?
The lipid membrane stores the charge
Voltage is produced across the membrane
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How are charge and voltage different?
Charge = current x time
Voltage = charge stored / capacitance (ability of the membrane to store charge)
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What is electrophysiology?
Recording the signals in excitatory cells = electrophysiology
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What is conduction velocity?
the speed at which propagation of the action potential occurs
Measured in metres/second (m/s)
Can be as fast as 100m/s or as slow as 1m/s
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What are saltatory conductions? What does myelin do?
Saltatory conductions (from the latin for leap) propagation of AP along the axon from one node to the next, increasing the conduction velocity
Myelin insulates and prevents charge through ion channels
Local circuit current cause depolarisation of adjacent node of ranvier: new action potential initiated
Nodes occur at intervals of 0.2 - 2mm along the axon
Action potentials propagate quickly in myelinated nerves – up to 100m/s
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What are the 3 factors that effect conduction velocity?
Myelination of the axon
Good insulator
Increases speed of AP propagation
Diameter of the axon
The finer the fibre the slower it conducts
Fine fibres are invariably unmyelinated
Demyelinating conditions
Decrease conduction velocity in affected axons
Can eventually result in block of conduction
Will cause axonal death in the long term
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What are the causes and symptoms of central neuropathies?
Causes largely unknown but associated with:
Genetics
Being female
Some viral infections
Disruption of myelin sheaths in CNS neurons
Progressive symptoms:
Numbness and tingling
Progressive muscle weakness
Mobility problems
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What are the causes and symptoms or peripheral neuropathies?
Causes can include:
Campylobacter
Influenza virus
Cytomegalovirus
Epstein-barr virus
Disruption of myelin sheaths in PNS neurons
Symptoms: (can progress rapidly)
Pins and needles in the hands and feet
Limb weakness
Uncoordinated movement
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What is extracellular recording of action potentials? What is a compound action potential?
Compound action potential = action potentials recorded from a group of neurons
Previous diagrams relate to single cell intracellular recordings
Extracellular electrodes record from populations of neurons
Two electrodes measure the charge in relation to each other
Stimulate whole nerve therefore measure bulk flow of charge across two electrodes
Sum of potential changes as APs propagate down axons
A biphasic compound action potential
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What is the study of nerve conduction called?
Electromyography
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What is meant by nerve conduction being a graded phenomenon?
AP recorded from single fibre is all or none
Compound AP recorded from whole nerve not all or none, they are graded
Graded dependent on size of the stimulus
Small stim – few fibres – small potential
Larger stimulus – more fibres – larger potential
Maximum stimulus – all fibres – max potential
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What is meant by 'threshold' nervous conduction?
Degree of polarisation that triggers action potential
Varies between different neurons
Varies between different parts of the same neuron
Generally speaking: thicker fibres have lower thresholds (ie easier to stimulate action potentials)
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What affect does Tetrodotoxin (TTX) have on Na+ channels?
TTX occurs naturally in pufferfish
Poison (more lethal than cyanide)
Highly potent and selective
Specifically blocks Na+ channels
Binds to extracellular side of Na+ channel
Causes respiratory paralysis
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What affect foes tetraethyl ammonium (TEA+) have on K+ channels?
Potassium channels are the most widely distributed type of ions channel and are found in virtually all living organisms
Tetraethylammonium (TEA+) non specific potassium channel blocker
What would you expect an action potential to look like in the presence of TEA+?
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What were the salisbury poisonings of 2018?
March 2018 – 2 people unresponsive on a park in Salisbury
An assassination attempt to poison a former Russian military officer and double agent for the British intelligence agencies
Porton Down – Britain's biological and chemical research establishment
Labs on site identified A234, a military grade nerve agent from the Novichok family developed by the Soviet Union in the cold war
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What are the novichok poisons and how do they work?
A group of nerve agents
Mechanism inhibits acetylcholinesterase
Spasm/prevents relaxation of muscles (cardiac and respiratory)
Cause of death asphyxiation or cardiac arrest
Fast acting
Remain poisonous for a long time periods
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