NERVES AND MUSCLES VIVAS

Nerves2011-2, 2010-1Describe the resting membrane potential of a cell- There is difference in electronic charge across a cell membrane- The inside is negative compared to the outside- Resting MP results from separation of positive and negative charges across a cell membrane- Neuron average RMP -70 mV (about the equilibrium potential for K+)

What conditions are required to create a resting membrane potentialAcross the lipid bilayer:1. Must be an unequal distribution of ions across the membrane (creating a concentration gradient)2. The membrane must be permeable to one or more of those ions (i.e. ion channels)

In a neuron what ions are involved and how is the concentration gradient produced- K+ and Na+- K+ is primarily intracellular and Na+ extracellular- Passive movement of ions occur via selective ion channels- More (leak) K+ channels open at rest so K+ is prime determinant of the RMP- Na-K ATPase actively move ions against their electrochemical gradient to maintain RMP

2007-2, 2005-1, 2003-1Draw and label an action potential of a neuron

2010-1, 2007-2Describe the ionic fluxes during the action potential

2007-2

1. RMP(-70mV);2. Firing potential (-55mV)3. Voltage gated Na channels open

–> Depolarisation and overshoot: 0mV -> +35mV

4. Na+ channels close (inactivated state) and voltage gated K+ channels open (slower to open)

5. Na+ back to resting state6. After-hyperpolarization (K+

channels slower to close)7. K+ channels close -> RMP

Fast voltage gated Na channels - influx- Rapid increase due to positive feedback- Then repolarization by:

1. Rapidly to inactivated state (ARP)2. Gradient reversed during overshoot3. K+ channels open

Slower voltage gated K+ channels - efflux- Negative feedback- Slower to open and close- Causes hyperpolarisation - (which de-inactivates the Na-channels)- Hyperpolarisation = RRP

Where are ion channels distributed in myelinated neurons- Voltage gated Na+ concentrated at nodes of Ranvier and initial segment of myelinated neuron- Na+ channels are flanked by K+ channels involved in repolarization

2003-1Discuss the factors that affect conductionMyelinated vs unmyelinated- Myelin, a protein–lipid complex that is wrapped around the axon- Peripheral nervous system: Schwann cell wraps its membrane around an axon up to 100 times- CNS most neurons are myelinated by oligodendrocytes rather than Schwann cells - Unmyelinated: surrounded by Schwann cells without the wrapping of the Schwann cell membraneA, B are mylenated, C are unmyelinated

Saltatory vs non-saltatory- Myelinated nerves can conduct up to 50x faster- The AP will jump (via a current sink) from node to node (of Ranvier)

Size- Larger diameter = faster conduction- Larger: proprioception, somatic motor function, conscious touch, pressure- Smaller: pain and temp, autonomic function

Direction of the conduction- Orthodromic conduction is natural synapse/receptor -> along axon -> to termination- Antidromic is in the opposite direction – prevented by synapses (conduction only permited in one

direction)

Extra: “All-or-none” law- Once the AP is generated it will have constant amplitude and form, no increase in stimuli

will change the AP (note- this is for a single neuron, no a nerve containing many)

Extras:- Theshold intensity varies with duration - weaker need longer, stronger less time, as per strength-

duration curve- Slowly rising current may fail to generate AP due to adaptation- Local response: subthreshold stimuli -> local electrotonic potentials- Excitability is the reciprocal of threshold- Absolute refractory period “occurs from the time of firing until repolarization is about 1/3 complete)- Mixed nerves contain neurons of many sizes w/ different thresholds, a small stimulus -> small AP,

maximal stimulus -> maximal AP

2011-1What are the different types of nerve fibres (What classifications are there)Myelinated vs un myelinated- Myelin, a protein–lipid complex that is wrapped around the axon- Peripheral nervous system: Schwann cell wraps its membrane around an axon up to 100 times- CNS most neurons are myelinated by oligodendrocytes rather than Schwann cells - Unmyelinated: surrounded by Schwann cells without the wrapping of the Schwann cell membraneA, B are mylenated, C are unmyelinated

Saltatory vs non-saltatory- Myelinated nerves can conduct up to 50x faster- The AP will jump (via a current sink) from node to node (of Ranvier)

Size- Larger diameter = faster conduction- Larger: proprioception, somatic motor function, conscious touch, pressure- Smaller: pain and temp, autonomic function

ClassificationsGasser ABC (A – αβγδ), A and B myelinated, C unmyelinatedNumerical (sensory neuron) Ia, Ib, II, III, IV- Aα (Ia) are large myelinated somatic motor or proprioception- Aδ (III) are smaller pain and temp fibers

What is the clinical relevance to emergency medicinePain fibres are smaller and better penetrated by local anaesthetic leading to loss of pain before loss of touch or proprioception

Susceptibilty to: Most Intermediate LeastHypoxia A B CPressure B A CLocal anaesthetic C B A

Skeletal muscle

Definitions and FactsThick filament – myosin II, cross bridges w/ actin and have a catalytic site that hydolyses ATPThin filament – Actin in long double helix, w/ troponmyosin convering binding site at restTroponin T – binds the troponin to tropomyosinTroponin I – inhibits the interaction of actin with myosinTroponin C – contains the binding site for Ca2+

RMP of muscle -90mVAP lasts 2-4ms, conducted at 5m/s, ARP 1-3ms, prolonged after-polarizationSacroplasmic reticulum – membrane around cell, carries AP, stored Ca2+, involved in metabolismT tubules – part of sarcotubular system, carries AP between the individual fibrilsTerminal cisterns – in close contact T tubules near A-I band junctionIsometric contraction – same length contractionIsotonic contraction – same forceEccentric contraction – the muscle lengthens as they contractBecause work = force x distance isometric does no work (and does negative work if eccentric)Fibrillations – single fiber contraction due to denervation and increased sensitivity to circulating AchFasiculations – contractions of a group of fibers due to pathologic discharge of spinal motor neuronsMotor unit – a single motor neuron and all the muscle is innervates (will be of the same type)Size principal – recruitment is ordered, S before FR before FF

Metabolism:

Also: Creatine (rest/exercise) phophorylcreatine creatinine

O2 Debt- Anaerobic metabolism allows more work

(6x) to be done than could otherwise if completely dependent on O2 delivery

- After the period of exertion, the accumulated lactate will be broken down and ATP replenished by increased O2 consumption

- If lactate builds too high then enzyme inhibiting pH will develop

2009-2, 2008-2, 2005-1

Describe the sequence of events in contraction and relaxation of skeletal muscle

2008-2, 2007-2What is summation of contractions1. The electrical response of a muscle fiber to repeated stimulation2. Contractile mechanism does not have a refractory period, so repeated stimulation before

relaxation has occurred produces additional activation and a response added to the contraction already present

3. With rapidly repeated stimulation, individual responses fuse into one continuous contraction (tetanus; tetanic contraction)

4. Complete tetanus: no relaxation between stimuli; tension developed ~ 4 times that of an individual twitch contraction

5. Incomplete tetanus: periods of incomplete relaxation between summated stimuli

Nb: stimulation frequency determined by the twitch duration- so if twitch duration = 10ms, <100/s discrete responses, >100/s will cause summation

How does tetanus differ from Treppe 2007-2Treppe (which means staircase in German)- Series of maximal stimuli at a frequency just below tetanizing -> increasing tension between each

twitch- Due to increased Ca2+ availability in sarcoplasm- Cause for the force-frequency relationship in myocardial contractility

What are the major differences in types of skeletal muscle 2007-2- slow and fast, containing a mixture of type I, IIa and IIb- fast fibers may have twitch duration ~7.5ms, for fine, rapid precise movements- slow fibres may have twitch duration up to 100ms, for strong, gross sustained movements

Type I (SO) Type IIa (FOG) Type IIb (FG)Other name Slow oxidative red Fast oxidative glycolytic Fast glycolyticColour Red Red WhiteMyosin ATPase Slow Fast

HighLargeHigh

Ca2+ pumping ModerateDiameter SmallGlycolytic Capacity ModerateOxidative Capacity High Moderate LowMotor Unit Slow (S) Fast fatigue resistant (FR) Fast fatigable (FF)

Cardiac muscleRMP -90mVAP – depolarization 2ms, but very long plateau and repolarization 200ms (contraction half over)Intercalcated disks – Connect interdigitated cells for strengthGap junctions - Low resistance bridges for excitation as a syncytium (but no cytoplasmic connection)T tubules are at Z lines (c.f. skeletal at A-I junction)

0 - Rapid depolarization, INa opens, fast Na+ influx1 - Rapid initial depolarization, INa closes2 - Plateau phase, Ca2+ influx (slow)3 - Slow repolarization, IK , K+ efflux (slow)4 - RMP

ARP is thus long – 200ms, and RRP until phase 4This prevents tetany

Smooth muscle

2007-1Describe the sequence of events in contraction and relaxation of visceral smooth muscle

Contraction of unitary SMCs stimulated by:1. Stretch muscle causes contraction in the absence of innervation (membrane potential spikes)2. Cold increases activity3. ACh decreases smooth muscle potential and increases spike frequency so resulting in more

active muscle4. Adrenaline and noradrenaline increase smooth muscle potential and decrease spike frequency

causing decreased muscle activity5. Neural

Smooth muscle (vs skeletal)- No striations, instead dense bodies- Tropomyosin, no troponin- Isoforms of actin and myosin are different- Unitary (visceral): large sheets, gap junctions, syncytial

(e.g. hollow viscera: intestine, uterus, ureters)- Multiunit: individual units, no gaps, en passant nerve endings to

each cell, for fine (non-voluntary) control (e.g. iris of eye)Tone- Maintained in partial state of contraction- No true RMP (-20 to -65mV), higher if active, lower if inhibited

Force generation- Despite 20% less myosin and 100 fold less ATP useage…- Can generate as much tension as skeletal m. per cross-section- Contractions are much slower

Plasticity- If stretched, initially tension increases- After time it relaxes and tension falls (possibly even below initial)

(e.g. the bladder wall w/ increased volume)

Synaptic and Junctional Transmission

Definitions and FactsEPSP – excitatory post synaptic potential, begins 0.5ms, peaks 11.5ms, declines exponentially, due to openings of Na+ or Ca2+ channels, not enough for generation of a full action potential, but can summateIPSP – the opposite, due to increased Cl- or opening K+ channels or closure Na+ or Ca2+ channelsTemporal summation – repeated EPSPs prior to decaySpacial summation – if activity present at more than one synaptic knob- the EPSP is not an “all-or-none” response, but a graded proportional response to the strength of

afferent stimulusOcclusion – the sharing of post-synaptic neurons results in a decrease in expected responseSlow synaptic potentials – in autonomic ganglia, cardiac m. SMC, cortical neurons, latency 100-500ms last several seconds, due to K+ conductance

2010-1, 2006-2In the synapse where can inhibition occur1. Post-synaptic (direct due to IPSP, or indirect due to previous post synaptic discharge)- E.g. in the spinal cord the reflex contraction to the agonists at the same time caused inhibition of

the antagonists (reciprocal innervation via interposed inhibitory neuron)2. Pre-synaptic- Via neuron that ends on excitatory endings (axoaxonal synapse)- By 3 mechanisms:

i. GABA -> intracellular Cl- -> decreasing AP, of Ca2+ and therefore transmitter releaseii. Voltage gated K+ channels -> also decreases Ca2+ entryiii. Direct inhibition independent of Ca2+

Neuromuscluar transmission

Neuromuscular junction: endfeet containing vesicles with acetylcholine insert into junctional folds on the motor endplate

AP -> increased permeability to Ca2+ -> triggers exocytosis of acetylcholine vesicles -> diffuses to nicotinic receptors -> increased Na+ and K+ conductance -> depolarizing endplate potential

The acetylcholine then removed by acetylcholinesterase (high conc in NMJ)

Smooth and Cardiac muscle- Multiple branches of noradrenergic (?cholinergic) are beaded with varicosities allowing 1

discharge to innervated many effector cells- Synapse en passant: the neuron make synapses, then passes on to make more synapses –

supplying many muscle fibres- EJPs: excitatory junctional potentials are seen by stimulation with the neurotransmitter

(noradrenaline or acetylcholine depending on tissue) as discrete potentials (like endplate potentials) and can summate with repeated stimuli

- IJPs: the opposite, hyperpolarizing, seen in tissues inhibited by noradrenaline

Denervation hypersensitivity- Increased sensitivity to acetylcholine after dennervation- Skeletal m. atrophies also, SMCs don’t, but become hypersensitive to activating mediator- Limited to the structures immediately innervated by destroyed neurons, i.e. supra segmental

spinal lesion doesn’t cause hypersensitivity to paralysed skeletal muscle- Multiple causes: upregulation of receptors, and reduction in mediator reuptake