Nervous system

Action potential

Rapid, reversible change in membrane potential, consisting of a depolarisation follow by a repolarisation.

Model organism/species

Squid!!! They have a giant axon (1mm diameter) used by Hodgkin and Huxley.

Voltage clamp

Electronic device that allows measurement of whole-cell ionic currents. Operates by setting the membrane potential to a predetermined value and measuring the charge needed to get there.

Nerve cell resting potential

\-70mV

Properties of action potential

Voltage-dependent and all-or-none

Uncoupling membrane potential and ion permability

Voltage clamp function, in order to measure cell current

Rising phase/depolarisation (AP)

Increasing membrane permability to Na+. The overshoot heads towards ENa.

Repolarisation (AP)

Na permeability falls, K permeability rises.

Hyperpolarisation (AP)

K permeability remains for several milliseconds after the spike. Vm heads towards Ek

Voltage-gated cation channels

K, Na and Ca ion channels each made of 4 homologous polypeptide domains which join to form a pore. E\~ach domain is made of 6 alpha helix segments.

Selectivity

Negatively-charged amino acids are found at the intra/extracellular openings of segments 5 and 6 to repel anions.

Snug-fit model (selectivity)

Selectivity filter contains for carbonyl oxygen atoms which can bind with K+ to remove the water of hydration, allowing the smaller, dehydrated K+ to pass through. Na cannot pass as it is unable to form enough bonds with the oxygen to remove all of the water, therefore too large.

Voltage sensitivity

Segment 4 of each domain has positively-charged amino acids that move outwards when the membrane depolarises to open the channel.

Hodgkin cycle

Positive feedback process where the opening of \`Na channels in a segment allows more \`Na to move into the cell causing more depolarisation and hence more Na channels open.

Inactivation

Loop of amino acids (‘ball-and-chain in K channels) swings up to block the channel on the cytoplasmic side. Cue for inactivation is the original depolarisation, but inactivation takes time, vice versa for re-activation.

Differences between channels

Sodium channels have faster opening repsonse to depolarisation than potassium. Na channels also inactivate far more quickly (1-2 millisec)

Stochastic

Describes the behaviour of individual channels, only the probability of their state can be determined, based on membrane potential and its immediate history. However the collective behaviour of many channels is predictable.

Activation threshold

The initial depolarisation such that the Na entry exceeds K loss, causing the positive feedback Hodgkin cycle.

Absolute refractory period (ARP)

Time-period after the beginning of an AP when a second AP cannot be generated, no matter the stimulus size.

Relative refractory period (RRP)

Time in which a second AP can only be elicited with a stimulus of greater amplitude than normal, as a proportion of the channels are inactive, so a higher fraction of the available channels must be activated.

Local circuit current

Positive charge (not exact ions) spreads as driven by potential gradient, this depolarised the next segment of membrane, positive ions leave the extracellular side to complete the circuit causing Hodgkin cycle. Inactivation ensures unidirectionality.

Electrotonic propagation

Passive process where a given depolarisation declines in size over distance. Na+ entry reinforces the signal at each successive axon segment.

All-or-none

If the original stimulus was above threshold, successive self-reinforcement means the AP amplitude at any distance will always be equal.

Electric analogue model

Each segment of an axon can be represented as 3 resistors and a capacitor.

Re

External resistance due to extracellular fluid: negligible.

Ra

Axonal resistance: inversely proportional to cross-sectional area.

Rm

Membrane resistance per unit length of axon: inversely proportional to membrane area and density of ‘background’ ion channels.

Cm

Membrane capacitance: proportional to surface area.

Adaptations for efficient propagation

To lose less current: Less ‘leaky’ membrane and wider axon, for easier current flow.

Length constant (Lamda)

Distance over which the voltage change caused by an injection of current at distance x=0 decays to 37% (1/e) of its original value.

Time constant (Tao)

Time taken for the membrane potential to rise from baseline to 63% of its final, asymptotic value at x=lamda.

Myelin sheath

Layers of specialised cell membranes wrapped several hundred times around a nerve axon. From Schwann cells in the peripheral nervous system, from oligodendrocytes in the CNS.

Nodes of Ranvier

Non-myself aged sections between myelin internodes.

Internodes

Myelinated regions of a nerve axon.

Saltatory conduction

The ‘jumping’ of an AP by means of an extended local circuit current between Nodes of Ranvier, due to the restriction of transmembrane sodium currents to the nodes.

Safety factor

Myelination increases the length constant longer than it needs to be, so several nodes are excited at once during the AP.

Factors affecting AP conduction velocity

Behaviour/density of voltage-gated ion channels, warmer temperatures (inc), larger length constant (inc), smaller time constant (inc).

Metabolic advantage of myelin

Fewer Na+ cross the axons membrane therefore fewer ions need to be pumped back out by Na+/K+ ATPase.

Squid giant axons

Used to stimulate mantle muscles to coordinatedly contract, part of their jet-propulsion escaper response. Diameter 1mm, conduction 25m/sec.

Human axons

Diameter 20micrometers, speed 120m/sec.

Synapse

Specialised region of communication between two cells, at least one of which is excitable.

Electrical synapse

Ionic current can pass directly between two cells via gap junctions. Found in smooth muscle cells, cardiac muscle cells and some neurons.

Ionotopic transmission

Fast chemical synapses (still incur delay, 0.5-2 msec) where ion channels are opened directly.

Metabotropic transmission

Slower chemical synapses which involve second messengers to modulate ion channel activity.

Alpha motor neuron

Contains cell body in the ventral horn of the grey matter (non-myelinated) of the spinal cord. Has a large, myelinated axon as part of a somatic motor nerve to innervate skeletal muscle. At destination, axon divides to form NMJs with several msucle fibres.

Motor unit

All the muscle fibres innervated by the same axon, can very from a few to a few hundred.

Neuromuscular junction

Consists of branching axon terminal, contained within a gutter in the muscle fibre membrane (post-synaptic membrane\`). Covered by the cytoplasm (but not membrane) of the last Schwann cell (supports physically and chemically). Also referred to as motor end plates.

Terminal bouton

Multiple swellings within the end-plate of the axon, release neurotransmitter acetylcholine.

50 nm

Width of a synaptic cleft.

Synaptotagmin

Calcium sensor found on the membrane of secretory vesicles. Promotes interaction between target-membrane SNARE (t-SNARE) and vesicle-membrane SNARE (v-SNARE). Leading to exocytosis.

Action at terminal bouton

Depolarisation causes voltage-gated calcium ion channels to open, these are located close to the active zone where synaptic vesicles are held.

Nicotinic acetylcholine receptors (NAChR)

Ligand gated ion channels with a high density on the crests of junctional folds. Pentameric structure in adult mammals.

Action of NAChR

One ACh must bind to each of the 2 alpha subunits causing conformational change and channel opens. Allows Na+ and K+ to pass (opposite directions) causing depolarisation 30 times faster than Na+ channel.

Botulinum toxin (Botox)

Neurotoxin that prevents presynaptic release of acetylcholine

End-plate potential (EPP)

Depolarisation of the post-synaptic membrane at about 20-40 mV, and propagates electrotonically and hence locally to nearby Na channels.

Tubocurarine

Drug used to reduce the size of an EPP below threshold so that an action potential is not generated and the hump of the EPP can be measured.

Miniature end-plate potentials (mEPPs)

Spontaneous release of singular vesicles fusing with the pre-synaptic membrane (0.4mV potentials). Stochastic event following a Poisson distribution.

Acetylcholinesterase

Enzyme that breaks down the released ACh to choline and acetate.

Choline recycling

Choline is actively transported across the pre-synaptic membrane and recycled into ACh using acetate from acetyl coenzyme A

Terminating response

ACh break down by acetylcholinesterase, new vehicles made by endocytosis, transporters fill them with newly synthesised ACh, Ca2+ is actively pumped out of the terminal of the nerve.

Central neurons

Neurons that work by integrating information from multiple synaptic inputs into their branching dendrites.

Excitatory post-synaptic potentials (EPSPs)

Small depolarisations of the dendrites, increase the probability of reaching threshold and AP firing. Temporal and spatial summation occur which can be large enough to bring the membrane to threshold.

Inhibitory post-synaptic potentials (IPSPs)

Decrease probability of cell reaching threshold, sometimes hyper polarising. Use GABA (brain) or glycine (spine) to increase Cl- permeability

EPSPs and IPSPs

Axon initial segment

Site of AP initiation on a central neuron, located past the axon hillcock. Has a high density of voltage-gated Na channels.

Myogenic

Electrical signals generated by muscle rather than nerve impulse. Like APs generated by cardiac muscle cells.

Sinoatrial node (SAN)

Pacemaker of the heart: group of modified, non-contractile myocytes within the wall of the right atrium. Connected to normal cardiac myocytes by gap junctions. (SAN ensures coordination)

Pacemaker potential

SAN cells do not have a resting potential, as their membrane slowly and spontaneously depolarises due to influx of Na (funny current) followed by Ca (through L-type voltage-gated Ca channels). This can initiate an AP.

Repolarisation of SAN cells

Occurs when calcium channels inactivate and K leaves via voltage-gated ‘delayed rectifier’ channels

Autonomic nervous system and SAN

Controls the slope of the pacemaker potential and heart rate.

Autonomic nervous system (ANS)

Innervates smooth muscle, cardiac muscle and various secretory glands. 3 divisions: sympathetic, parasympathetic and enteric, with the first two both being efferent.

Alpha motor neurons

Nerve fibres that supply skeletal muscle, cell bodies reside in the ventral horn of the grey matter of the spinal cord. (Somatic nervous system)

Ventilation

Involved in the homeostatic control of blood gas concentrations and pH, requires the use of the skeletal diaphragm and chest-wall muscles.

Shivering

Homeostatic control of body temperature mediated by skeletal muscles.

Preganglionic neuron

Myelinated neurons with a cell body in the CNS. Sends axon to an **autonomic ganglion**, where there is a cholinergenic synapse. In both sympathetic and parasympathetic.

Postganglionic neurons

Cell bodies in the ganglion and unmyelinated axons innervate the muscle/gland in question.

Difference between parasympathetic and sympathetic nerve fibres

Sympathetic= short preganglionic and long postganglionic. Releases adrenaline or noradrenaline

Parasympathetic= long preganglionic and short post ganglionic. Releases ACh at terminal to a muscarinic receptor.

Terminal varicosites

Used in place of a NMJ, acts as a ‘neuroeffector junction’ with the target tissue.

Sympathetic nerve fibres

Cell bodies in the intermediolateral column of the spinal cord grey matter. Axons are sent out via the ventral root.

Noradrenaline

Released as a neurotransmitter by postganglionic neurons, also released by the adrenal medulla but does not have a physiologically significant effect and hence is not considered a hormone.

Adrenaline

Some preganglionic sympathetic fibres synapse onto chromaffin cells in the adrenal medulla, ACh causes these cells to release adrenaline into the blood (endocrine arm of the SNS)

Chromaffin cells

Specialised ganglion cells

G-protein coupled adrenergic receptors

Receptors affected by adrenaline and noradrenaline.

Alpha-2 and beta-2

Receptors for which adrenaline is more potent

Alpha-1 and beta-1

Receptors for which noradrenaline is more potent

Caltecholamines

Grouped name for adrenaline and noradrenaline

Beta receptors

Coupled to excitatory G-proteins which increase cAMP as a second messenger inside the cell via adenylate cyclase

Cyclic AMP

The second messenger in G-protein coupled receptors

Alpha 1 receptor

Works via Gq to activate the inositol phospholipid pathway

Inositol phospholipid pathway

Key pathway within cell signalling

Alpha 2 receptor

Receptor coupled to an inhibitory G-protein inside the cell, which impacts adenylate cyclate to produce less cAMP

Factors affecting the effects of adrenaline

1. Which cells express adrenergic receptors
2. How many are expressed
3. What kind they are

Preganglionic parasympathetic fibres

Myelinated fibres that emerge from the brain and are carried within cranial nerves to their target organs.

Vagus nerve

Nerve which supplies parasympathetic innervation to most of the thoracic and abdominal organs.

Synapse of preG parasympathetic fibres

Synapse either in a ganglion close to the target organ or within the wall of the organ itself. (ACh acts on NAChR at the synapse)

Muscarinic cholinergenic receptors

Receptors for which the postganglionic fibres of the parasympathetic nervous system release ACh (or sometimes vasoactive intestinal peptide or nitrogen oxide)

Atropine

Drug which blocks muscarinic receptors.

Enteric nervous system

Responsible for gastrointestinal innervation, for example the parasympathetic postganglionic fibres going to the gut belong to it.

Heart at rest

Receives tonic parasympathetic stimulation from the vagus, but little if any sympathetic stimulation.

Effect of catechomines on the heart

Beta-1-adrenoreceptors on SAN cells respond to adrenaline and noradrenaline by activating an excitatory G-protein, leading to an increase in intracellular cAMP. This results in Na and Ca channels opening, speeding up the rate of depolarisation and therefore heart rate.