Neuro physiology Flashcards
% TBW
How much is ICF
How much is ECF
of the ECF how much is vascular and how much is interstitial
60% of body weight
- 40% is ICF
- 20% is ECF
of the ECF
25% vascular (i.e 5% of TBW)
75% interstitial (i.3 15% of body weight)
What is ECF best measured using
Inulin which is a polysaccharide
MW5200
Comment on ICF/ECF osmolarity
ECF is iso-osmotic
ICF is at osmotic equilibrium
How do we calculate ICF
Using TBW-ECF
(measure TBW with D20)
What is TBW inversely proportional to
fat
4 fundamental properties of the cell membrane
- semipermeable membrane
- permeable to water, Na, K, Ca, etc… - preferential permeability to lipid-soluble substances
- low surface tension
- high electrical resistance practically impermeable to organic anions
What are the 4 ways substances can cross a membrane
- Diffuse freely
- If small and uncharged
- e.g N2, O2, CO2 - Endocytosis
- Clathrin mediated - Exocytosis
- Via transport proteins
- Glucose
- Urea
- Amino acids
- Water
how well a substance crosses the membrane depends on.. (3)
- Size (smaller the better)
- Electrical charge on surface of substance (positive preferred, negative is repelled)
- Lipid solubility (fat=good)
What factors determine the gate like activity of transport proteins
- Charge
- voltage gated Na channel - Activating substance
- ligand gated
- e.g hormone, neurotransmitter or internal ca, CAMP - Carrier protein (things to carry it across a channel)
- Things normally move by an electrical or chemical gradient.
- Active transport would be against a concentration gradient, facilitated diffusion would be down a conc gradient (like glucose)
Define uniport, symport and antiport
Uniport:
- Movement of one molecule independent of the other molecules is known as a uniport.
Symport:
- Movement of two molecules in the same direction through a protein channel is known as symport.
Antiport:
- Movement of two molecules in the opposite direction through a protein channel is known as antiport.
What is the Donnan Gibbs effect and what would its implication be if equilibrium was reached
Describes the tendency of diffusable ions to distribute themselves such that the ratios of the concentrations are equal when they are in the presence of non-diffusable ions.
In the presence of impermeable anions. Positive ions will shift into the intracellular compartment to try to equalise the difference in charge, whilst the negatively charged ions will be repelled by its electrical gradient but attempt to move into it via its chemical gradient.
At Gibbs Donnan equilibrium…
On each side of the membrane each solution will be electrically neutral (i.e the net balance of positive and negative charged within each compartment will balance). But there will an unequal distribution of total ions (ie chemical) and slight charge difference across each membrane.
Is the cell membrane more permeable to K or Na
K
What is the RMP of nerve and muscle
-70 to -90
What impact does insulin have on RMP
Increases RMP (hyperpolarization)
Why is scurvy associated with blood vessel fragility
Because ascorbic acid is an essential cofactor for the synthesis of collagen
Are liver capillaries permeable to plasma proteins
Yes
How does glucose transfer across the capillary wall
Passive diffusion
Is the Gibbs Donnan effect the same as RMP
No they are different mechanisms.
The Gibbs Donnan effect is a PASSIVE process, whilst the RMP is maintained by Na/K/Atpase
What is serum osmolality
300
What happens when extracellular K concentration is reduced to 3
- K+ will diffuse out of the cell
- H+ will diffuse into the cell
- The intracellular net charge will remain unchanged (Donnans effect)
Compare Na, Mg, Cl and protein concentrations between interstitial fluid and plasma.
Na: Higher in plasma
Mg: Higher in plasma
Cl: Higher in interstitial fluid (Donnan)
Protein: Higher in plasma
What are the concentrations of Na and K in intracellular fluid.
What is the other main cation present.
What is the main anion inside the cell.
Comment on H+ concentration compared to extracellular.
- K concentration is ~ 150 - 160
- Na concentration is 15
- organic phosphates are present in high (i;e chloride isnt the main anion, again due to Donnans)
- the H ion concentration exceeds that in extracellular fluid (Donnans)
What is the interstitial concentration of Na, K, and CL
Na 150
K 5.5
CL 125
What are tight junctions.
Where are they found and what is there purpose.
What proteins contribute to them.
Also known as Zona Occludens
A form of intercellular connections that ties cells together and endows strength to tissue.
They are found just below the luminal surface.
They characteristically surround apical margins of cells in epithelia.
(wall of renal tubules, intestinal mucosa, choroid plexus)
They restrict molecular movement across epithelium and facilitate cell to cell adhesion (i.e they let some ions pass through the paracellular route depending on their leakiness.
Occudin, junctional adhesion molecules and claudins are the proteins that contribute to tight junctions.
What are gap junctions
What are they made of
What is their function (i.e what do they let through)
Where are they found
Gap junctions form a cytoplasmic tunnel for diffusion of small molecules between two cells (without entering the ECF).
Connexons in the membrane of each cell form the gap junctoin.
1 connexon (hemi channel) = 6 connexin subunits
They allow ions, sugars, amino acids and anything <MW 1000.
Denies access to larger or negatively charged molecules.
Facilitates cell to cell communication
Allows cardiac or smooth muscle to contract simultaneously.
What is a disease associated with defective connexin gene, how is it inherited and what does it cause.
Charcot Marie Tooth disease
X linked
Peripheral neuropathy
How do we regulate our receptors in response to a stimulus (e.g too much or too little hormone) and what is an exception to this
Down regulation
- Endocytosis
- Chemically desensitised
Up regulation
- When there is in sufficient hormone we increase teh number of active receptors
The exception to this being ANGII acting on the adrenal cortex. It increases rather than decreases the number of receptors.
What are the functions of second messengers
Change enzyme function
Trigger excytosis.
Alter transcription fo various genes
What is the function of Na/K/Atpase
Catalyses the hydrolyses of of ATP to ADP uses the energy to extrude 3 Na out of the cell and bring in 2 K.
I.e has a coupling ratio of 3:2
What inhibits the activity of Na/K/Atpase
Descreased ATP production
Oubain
Digoxin
Dopamine
What is the structure of Na/K/Atpase.
Heterodimer made up of a single alpha and beta sub units.
What stimulates the action of Na/K+ ATPase
high level of intracellular Na
Thyroid
Insulin
Aldosterone
How much energy does Na/K/Atpase use in cells and neurons
24% cells
70% neurons
Do we lose more sodium or K in our urine
Sodium
- As we have more of this in our extracellular fluid
Do men and women have different TBW
Yes, women have lower
Can TBW be estimated from measurement of plasma volume
No
Does TBW change with age
Yes, it decreases
What fluid comparment expands with hypotonic fluid
TBW expansion
- Dilutional hyponatremia
What compartment expands with isotonic fluid
ECF expansion
interstitial oedema, fluid overload
Response to injury include
Obligatory sodium and water retention
Transcapillary escape of albumin
Why don’t we replace potassium post op
Damage to tissue releases K+
What should you replace maintenance and losses with
Maintenance replace with hypotonic fluid (as this is what we drink normally)
Replace losses with a isotonic fluid
kwashiorkor and marasmus
- What are they
kwashiorkor is predominantly a protein deficiency, while marasmus is a deficiency of all macronutrients — protein, carbohydrates and fats.
4 Major adaptations to pure starvation
- Break down triglycerol in adipose
- Create new glucose in liver and kidney
- Make ketone bodies
- Break down muscle
Protein requirements a day
1.2-1.5 g/kg a day
Energy requirements for parenteral nutirion
~25kcal a day/kg a day
of which 15-30% is lipid
What hormones increase tyrosine kinase activity
Insulin
EGF
PDGF
M-CSF
What stimuli decrease adeynyl cyclase (and therefore decerase cAMP)
NA via A2
What stimuli increase adenylyl cyclase (and therefore increase cAMP)
NA via B1
Glucagon
Vasopressin
What stimuli increase phospholipase C
ANG II
NA via A-adrenergic receptor ADH via V1 receptor
What stimuli act vis cytoplasmic or nuclear receptors, increasing transcription of selected mRNAs
Thyroid hormones
Retinoic acid
Steroid hormones
What stimuli open or close ion channels in cell membranes
Ach on nicotinic
Na on K channel in heart
Why does intracellular oedema occur where blood flow is depressed
Because inadequate oxygenation depresses cell membrane ionic pumps and allows Na to leak into cells.
Compare intracellular and extracellular concentration of Ca (and where is it found in the intracellular compartment)
Intracellular 100nmol/L
- Mostly bound to Er and other organelles
- Organelles allow calcium to be stored and released when needed
Extracellular 1200x higher > therefore Ca always wants to get into the cell
How can Ca enter the cell from the ECF (i.e receptor types)
Down its electrochemical gradient through many different Ca channels.
- Ligand gated
- Voltage gated (which can be further divided into Transient or long standing types)
- Stretch activated
What are microtubules made of
What are their functions
Tubulin and make up part of cytoskeleton, they make up teh filaments of the spindle at mitosis and are not part of the golgi complex.
They fix the shape of platelets
They assist the transport of materials within the cell.
Where are lysosomes found
what disease are they implicated in
What do they form and how
Where are they released.
Found in granulocyte WBC
May be involved in gouty arthritis
Merge with intracellular membrane lined vacuoles containing exogenous substances forming a phagocytic vacuole
Are released intra-cellularly (Not extra-cellularly, in normal host response to infection to cause bacteriolysis)
What two ways can we bring Ca into the cell, and how do we replenish the store once used.
- Via channels (i.e bring from ECF into ICF)
- Or released from ER (increases free Ca in cytosplasm e.g Ryanodine receptors).
Transient release of Ca from internal store triggers the opening of a population of Ca channels in the cell membrane called SOCCs (store operated Ca channels). This results in Ca influx which refills the endoplasmic reticulum
How is calcium removed from cytoplasm
This process requires energy since we are moving against a concentration gradient.
Therefore this is facilitated with plasma membrane ATPases.
OR alternatively it can be transported by the Na/Ca antiport that exchanges 3 Na for every Ca.
The SERCA pump, is the sarcoplasmic or endoplamsmic reticulum ATPase.
What does Calcium need to bind to once in the cell.
A calcium binding protein
Troponin
- Involved in the contraction of skeletal muscle
Calmodulin
- Has 4 Ca binding domains
- When calcium binds to it it is capable of activating 5 different Calmodulin dependent kinases.
1. Myosin light chain kinase: Phosphorylates myosin which brings about contraction of smooth muscle.
2. CAMK1 and II - synaptic junction
3. CAMK III - protein synthesis
What is an RMP and what conditions must be met in order for this to occur.
Membrane potential refers to the voltage difference across the cell membrane of a neuron.
- There must be unequal distribution of ions of one type across the membrane (i.e conc gradient).
- The membrane must be permeable to these ions.
-70mv
It represents an equilibrium situation at which the driving force for the membrane permeant ions down their concentration gradient is equal and opposite to the driving force for these ions down their electrical gradients.
In our cells we have more K+ in cells and more Na+ outside. This is established and maintained by Na/K ATpase (as already outline if we didnt have this ions would continue to dissipiate)
I.e this means that K+ has a tendency to go out and Na to come in. However we have more K+ channels open at rest so membrane is more permeable to K.
What is the all or none theory
If threshold is not reached, nothing happens.
If threshold is reach an AP will occur (without any extra increment if we go well above threshold)
Compare metabolic rate of nerve and muscle during activity
Doubles in nerves
Increases by as much as 100 fold in muscles
Does inhibition of lactic acid help with nerve function
No it does not influence it
What is the refractory period divided into
Absolute
- Time the firing level is reached until repol is 1/3 complete
- NO stimulus will excite the nerve
Relative
- From time repol is 1/3 complete to the start of after depolarisation.
- Stronger than normal stimuli will excite the nerve.
Describe how an action potential occurs.
A depolarising stimulus causes some VOLTAGE gated Na+ channels to open.
This bring Na into the cell and makes it MORE positive bringing it to threshold potential (-55).
This causes a positive feedback loops, a lot more Na+ channels to open (more than K) and lots of Na enters the cell. The rapid upstroke in the membrane potential ensues.
The membrane potential moves towards the equilibrium potential for Na (+60).
Na receptors now become inactivated and the electrical gradient has shifted in the opposite direction (i.e we have a positive inside of the cell).
Voltage gated potassium channels now open down their electrical AND chemical gradient and repolarisation occurs.
The Na+ channels closing limiting influx and K+ channels opening both contribute to repolarisation.
Repolarisation occurs slower than depolarisaiton because the K+ channels open slower and for longer (this also explains why hyperpolarisation occurs)
How do we conduct an AP down a neuron
Inside of cell is negative at rest.
So when Na comes into the cell it propogates down its concentration gradient (meaning some does also propogate backwards).
This is improved by myelin which prevents Na from leaking out. depolarisation jumps from node to node ie saltatory conduction.
How do local anasthetics work
By blocking voltage gated NA channels
What are neurotrophins/ nerve growth factors
What makes them
How are they transported
What is their function
Proteins that are necessary for the survival and growth of neurons.
They are either produced by the muscles that they innervate or they come from astrocytes (in the CNS).
They bind to receptors at the NERVE ENDING, are internalised and then are transported retrograde back to the neuronal cell body. Other ones go from the soma to the nerve ending and maintain the post synaptic neuron,
From there they foster the production of proteins associated with neuronal development survival and growth.
They do NOT promote the growth of myelinated motor neurons
What are the 4 neurotrophins we know of and what receptors do they act on
Nerve growth factor
- trk A
Brain-derived neurotrophic factor BDNF
- trk B
Neurotrophin 3
- Trk C, Trk B
Neurotrophin 4/5
- trk B
Describe the structure of NGF and its function
A protein with 2 alpha, 2 beta and 2 gamma subunits.
Beta subunits have MW 13,200
- Has all the growth promoting activity
Alpha
- Trypsin like activity
Gamma
- Serine protease
Needed for growth and maintenance of sympathetic neurons and some sensory neurons.
What are the 3 types of pre synaptic vesicles and what do they contian
Small and clear
- ACh, glycine, GABA or glutamate
Small with dense core
- Catecholamines
Large with dense core
- Neuropeptides
Where are presynaptic vesciles made
Axonal body
transported along axoplasmic transport to nerve endings
How are presynaptic vesicles released into the synaptic cleft and what controls the release of these vesicles
Exocytosis into the synaptic cleft
Controlled by voltage gated calcium channels
What things block the release of pre synaptic vesicles
Zinc endopeptidases
- Inhibit proteins in the fusion exocytosis complex
Tetanus toxin
- Blocks presynaptic transmitter release in CNS
- Spastic paralysis
Botox
- Inhibits release of Ach at the NMH (flaccid paralysis)
Hypokalemia may be associated with (4)
1: flaccid paralysis
2. PR prolongation,
3. Prominent U waves
4. T wave inversion
5. paralytic ileus
6. polyuria (diabetes insipidus)
WHy does nerve generation result in an absent triple response to stroking
(and describe the stages)
The flare of the triple response is mediated by an axon reflex
Red spot, caused by capillary vasodilation.
Flare, a redness in the surrounding area due to arteriolar dilation mediated by axon reflex.
Wheal, caused by exudation of extracellular fluid from capillaries and venules.
What two types of receptors does ACh work on
Muscarinic (metabotropic, effects depend on subtype of receptor)
- CNS and PNS Visceral organs
- This is what atropine works on
Nictonic (inotropic) results in excitation of neuron
- Central nervous system
- NMJ
What type of neurons are cholinergic nerurons
- All pre-ganglionic neurons
- Parasympathetic post ganglionic neurons
- Sympathetic post ganglionic neurons that innervate sweat glands
- Sympathetic neurons that end on blood vessels in skeletal muscles and produce vasodilation when stimulated.
Structure of parasympathetic neuron
Long myelinated preganglionic
Short unmyelinated postganglionic
Please note there is no ganglion when parasympathetic innervates the heart
Structure of sympathetic neuron
Short myelinated preganglionic
Long unmyleinated post ganglionic
Describe the structure of the sympathetic nervous system.
The pregangionlic sympathetic neuron will always leave the spinal cord at the thoracic or lumbar region (T1-L2)
3 options once it leves
1. Synapse in para-vertebral ganglion
2. Not synapse, move up
3. Not synapse and move down
Some post ganglionic neurons sit in paravertebral ganglion and some sit closer to target neurons.
Superior cervical ganglion is the uppermost sympathetic ganglion.
Cervical ganglion innervate the eye and sweat glands
- Dilate pupil, open eyes
- Inhibit salivary secretion
- Inhibit lacrimal tears
T1-T4
- Preganglionic neurons synapse in the paravertebral ganglion. They leave the paravertebral ganglionic chain and will innervate the heart and respiratory tract.
T5-T9 = GREATER splancnic nerve
- Do not synapse in paravertebral ganglion
- They synapse in the coeliac ganglion
- Post ganglionic neuron, innervates foregut.
- With a branch going to the adrenal BEFORE it synpases.
T9-T11 = LESSER splanchnic nerve
- Synpase in coeliec ganglion
- Innervate small intestine.
- Branch of lesser splancnic can go to superior mesenteric ganglion - innervate large intestine excluding rectum.
T12 = LEAST splancnic nerve
- Renal plexus
Structure of parasympathetic nervous system
Cranial outflow
Oculomotor nerve (CN III) – iris, ciliary muscles
Facial nerve (CN VII) – lacrimal, nasal, palatine, pharyngeal, sublingual, submandibular glands
Glossopharyngeal nerve (CN IX) – parotid gland
Vagus outflow
Vagus nerve (CN X)
- Parasympathetic up to the splenic flexure
Sacral outflow
Pelvic splanchnic nerves – descending colon, sigmoid colon, rectum, bladder, penis or clitoris
All synapse at target organ
Outline how skeletal muscles contract.
Axon terminal of neuron contains vesicles which have neurotransmitter Ach.
Describe the structure of a skeletal muscle sacromere
Including the structure of actin and myosin
Which shorten during contraction.
The area between 2 Z lines is a sacromere i.e the functional unit.
Z line
- anchor for thin filament
- Moves closer together
M line
- anchor for myosin
I band
- shows actin filament only
- Shortens
A band
- Length of myosin (some of which is overlapped by actin ie contains thick and thin filaments.
- Stays constant
H band
- Myosin only (i.e the part of myosin that is not overlapped by actin)
- Shortens
Titin connects Z lines to M lines (acts like a spring).
Actin
- Polymers made up of 2 chains of actin that form a long double helix.
- Tropomysin: Long filaments in the groove between 2 chains.
- Troponin: Small globular units located alone tropomysin.
Myosin
- Contains two globular heads and a tail.
- Heads made up light chains and amino terminal portions of heavy chains.
Describe excitation contraction coupling and the sliding filament theory.
ACh released from NMJ, binds to Ach receptors on muscle.
Opens Na channels, sodium rushes in, depolarising the sarcolemma. propogates down the T tubules of muscle to get deep.
Depolarisation down the T tubule activates Dihydropyridine repceptors (Which are voltage gated Ca channels in the T tubule membrane), which is linked to the RYR receptor and Ca is released from the sarcoplasmic reticulum
Calcium then binds which releases the troponin/tropmysin complex uncovering the myosin binding sites on actin.
ATP bound to myosin disassociates to ADP and phosphate. This allows myosin to bind to actin and cock into position. ADP and phosphate are then released from Myosin. This allows myosin to stroke forward, sliding actin filaments together. ATP then rebinds which releases the head.
As long as calcium is available this cycle repeats.
The SERCA pump (sarcoplasmic reticulum Ca ATPase). Removes Ca from the cytosol against its concentration gradient. I.e ATP is required for both relaxation and contraction.
Isotonic vs isometric contraction
Isotonic muscle contraction produces limb movement without a change in muscle tension, whereas isometric muscle contraction produces muscle tension without a change in limb movement.
Isotonic contractions do work
Isometric contractions do no work
Describe summation of contractions
The contraction mechanism does not have a refractory period (unlike the neural component), therefore repeated stimulation before relaxation produces additional activation of contractile elements. These individual contractions can fuse together causing tetanus.
RMP in skeletal muscle
-90
How long does an AP last in a muscle and how fast is it conducted along a muscle fibre
how long is the refractory period
AP last 2-4 ms
Conducted at 5m/s
1-3 ms
What is a muscle twitch
and compare the duration of fast and slow twitch muscle fibres
Single AP causes brief contraction followed by relaxation.
- fast fibres twitch duration ~7.5ms
- slow fibres twitch duration ~100ms
Describe the cardiac action potential
The duration of the AP is longer when compared to a neuron.
RMP is -90
3 ions with 3 different channels play a role.
- Na channels = fast
- Ca = slow L type
- K+
Phase 0
- Depolarisation is from opening of sodium channels, upstroke occurs due to ~20. Some of this depolarisation can also be attributed to by calcium channels.
- Sodium channels get inactivated quickly.
Phase 1
- Initial repolarisation
- Na channels close and K+ channels open
Phase 2
- Plateau
- Ca channels remain open therefore depolarisation is sustained for a period of time.
Phase 3
- Late re-polorisation
- Calcium channels close
- K+ continues to leave cell
Phase 4
- Rest
- RMP is reached.
Actions potentials spread between gap junctions of cells,
Describe the action potential in electrical cardiac cells (SA node)
Cardiac conduction system is capable of self- excitation.
Phase 0
RMP of SA -55-60
Therefore anytime RMP becomes less negative than -55 the fast Na channels get inactivated so they dont contribute to depol. The L type Ca channels do (hence why it’s. Ca enters cell and depol occurs.
Phase 3
Ca channels close, K channels open. Re-polarisation occurs.
Phase 4
- Spontaneous depolarisation
- Na channels are able to leak into the cell taking RMO towards threshold of -40.
- Towards the later end of spontaneous depolarisation a different type of Ca channel open and contribute (T type).
Describe excitation contraction coupling in cardiac muscle.
Calcium ions enter sarcoplasm via L type calcium channel (on membrane of T tubule).
Triggers Ca RYR in sarcoplasmic reticulum.
Calcium binds to troponin C and sliding filament occurs.
Ions get pumped back into SR and ECF (by the use of SERCA2 pump), Na/ Ca is used to transport into ECF. Na is then pumped out via NA/K/ATPase.
If there is increased Ca entry there is increased Ca contractility (this happens when these channels are phosphorylated which is what the sympathetic nervous system does).
i.e Calcium induces the release of Ca (as opposed to Na in skeletal muscle)
Digoxin MOA
###
Catecholamines
###
Compare cardiac muscle morphology to skeletal
Z lines present but muscle fibres branch and interdigitate.
Nuclei are central as opposed to peripheral.
Intercalated disk occur where muscle fibres abut each other (which occurs at Z lines)
T system in cardiac muscle is located at the Z line as opposed to the A-I junction (like in skeletal muscle)
Compare smooth muscle morphology to cardiac and skeletal
- No cross striations
- Actin and myosin are present but not arranged regularly, instead of Z lines there are dense bodies.
- Contains tropomyosin but no ytoponin
- Les extensive sarcoplasmic reticulum
- Few mitochondria and depend on glycolysis.
- Calmodulin is the regulatory Ca binding protein
- The Ca pump is slow acting in comparison with the Ca pump in skeletal muscle
Smooth muscle contraction
- No fixed RMP
- Depoloarisation occurs due to calcium influx as opposed to sodium
- Calcium comes from variety of sources but predominantly from the ECF as opposed to sarcoplasmic reticulum as it is poorly developed and lacks mitochondria
Single unit smooth muscle can be stimulated to produce AP by
- Stretch
- Local factors like blood vessels (Contract in response to blood vessel constriction, relax in response to dilation)
- Decreased O2, increased CO2 and H+ = relaxation
- Hormonal (via ligand gated and GPCR)
Single unit
- Spike potential (like skeletal muscle)
- Action potential with plateau (like cardiac)
- Self generation of slow wave rhythm + spikes
Multi unit
- Junctional potentials instead of action potential that propagates along neighbouring cells.
- Do not spread widely like in single unit.
Smooth muscle contraction coupling and relaxation
Lack troponin therefore Ca bind to Calmodulin instead.
They also lack Z lines/sarcomeres so actin binds to dense bodies instead of Z lines.
Contains Calponin which is a calcium binding protien that INHIBITS the activity of myosin ATPase by binding to actin and tropomyosin.
When Ca binds to Calmodulin the complex and activates protein kinase that phosphorylates Calpoinin. Now inhibition is removed. This complex also activates myosin light chain kinase.
Myosin light chain kinase phosphorylates myosin to activate it, enabling it to bind to actin and cross bridge cycling to occur.
Relaxation
Calcium ATPase pump on Sarcoplasmic reticulum and on plasma mebrane to get rid of Calcium.
Na/Ca exchangers are also present.
Calcium unbinds from calmodulin but another step needs to occur for muscle to relax as the myosin is still phosphorylated.
The enzyme mysoin light chain posphatase is responsible for de-phosphorylating myosin.
