Neurophysiology Lecture notes
Lecture 1: Intro to neurons Ion channels: gated, ion selectivity and differen characteristics
- AP pattern determines message
Ion transporters Actively move ions against conc. gradient (create larger gradient), E depedent
- Na+/K+ pump : move K and Na against conc gradient
o 2 subunits ( alpha and beta ) alpha has Na+/K+ binding site, ATP
binding site
- Ca+ pump: move Ca+ against conc gradient with ATP
Ion exchangers
- Energy from Na+ to transport Ca+,K+,Cl-,H+,GABA
- Energy from K+ to transport cl-
Neural cells
- At rest selectively permeable to K+ ( leak channels) membrane potential ≈ K+ equilibrium potential
Ion selectivity of Voltage gated K+ channel
4 Subunits combine to form a pore to let ions through
Hydrated K ion line up in filter K leaves and another comes in
How does it differentiate with “ion selectivity filter”?
- The amino acids minics the oxygen (red) around K (green) as though it is in its relaxed
state/E efficient form
- K and water molecules always at the same distance in external environment aa will
be at same position
- Voltage, Ligand (neurotransmitter) and mechanical (deform)
- Gating hinge (red) to shift open and change structure
(E) Excitatory (F) Intracellular messengers
(C,D,E) one pore from 4 subunits (homo or heteromer)
(D) Inward rectifier- passes current (+ve/ K+) easily into the cell
- tend to work when the cell is hyperpolarised
- rectifier Permeability of ions change with voltage
What’s the characteristic of an K+ channel (leak)that can set the RMP?
Difference in movement of the K+ in the different ion channels
- Closes when its back to rest (underpins AP) o K+ Conductance is 0 at RMP Thus doesn’t set RMP
- opens and closes immediately, conductance 0 at rest, doesn’t
set RMP
o Doesn’t set RMP
- Inward rectifier –open by hyperpolarisation, conductance 1 at
rest determine RMP
- Open at rest
- Selective of K+
o THUS “inward rectifier” and “K2P” channels – not voltage gated ion channels
RMP important for function of neuron
- Resistance is the inverse of conductance
- Condutance= 1 fully open
Chloroform
LORR- loss of righting reflex (getting up from falling over) chloroform works by altering the channels TREK-2,
Inward recitfier and K2P thus contribute to RMP
Mouse without the channels need more chloroform to knock out
Lecture 2 NEURONS
- morphologically highly specialised
o Left :Purkinje cell highly branched
o Right: Pyramidal cell of cerebral cortex
- Highly synthetic protein producing cell ion channels, receptors and cytoskeleton
- Cytology shows a large pale nucleus and Nissl bodies (ribosomes, rough E)
Dendrites - Increase SA for synthetic input,lack major organelles
Axon - Up to 1m long
- Carry AP from cell body (hillock) or tip of axon (sensory neuron)
Volume of distribution High proportion in axons/dendrites damages usually at axon Structurals protiens
- Cytoskeleton
- Actin
o Spines(excitatory input) and growth cones
- Intermediate filaments
- Microtubules
Axon transport - Fast transport: membrane bound components (40cm/day)
o microtubule dependent +use kinesin
- Slow transport: Soluble material(4mm/day)
Samples of local environment
Virus/bacteria (exploit system)
Axon terminal Target cell: neuron or effector cell (muscle or secretory)
Synapse
- Postsynaptic density- receptors to respond to neurotransmitter
- Mainly supplied by axonal support
- Neurotransmitter release Ca+ dependent
o Diffusion of transmitter out of cleft
o Destruction of transmitter by enzymes
o Re-uptake of transmitter by target, axon and glial cell
Neuronal energy budget
- Brain metabolic demand
o Brain uses 20% of oxygen and 25% of glucose
o Sensitive to low blood flow (oxygen and glucose) little E reserves
o Brain sensitive to glucose but nerves only use lactate and pyruvate ( that can’t cross BBB)
- Activity dependent vasodilation(CNS)
o Synaptic activity increase blood flow increase glucose and oxygen
Shown in MRI and PET
GLIAL CELLS
- Lots of processes associated with blood vessels (astrocyte end-feet), dendrites, synapses
- Don’t overlap with other astrocytes connected by gap junctions
- ROLE:
o Blood vessel dilationSynaptic activity signal increase blood flow
o Neuronal E supply metabolise glucose for lactate/pyruvate into ECF
glycolytic pathway suppressed in neurons
o Synaptic plasticity
o Neurotransmitter recycling
o Protection from oxidative stress and injury recovery
Oligodendrocytes
o Wrap around and lays down myelin on cell membrane
o Nodes of Ranvier
- Activation: inflammation, injury (up regulate cytokines and growth factors)
- Lacking develop disease
o One axon per schwann cell
- Satellite cells – support nerve cell bodies in PNS ganglia
BLOOD BRAIN BARRIER
- BBB at capillaries , prevent free diffusion
o CSF low in K+, Ca and protein (diff to rest of body)
Lipophilic substance diffuse easily (heroin and nicotine)
- Usually other substances use active transport
Lecture 3: ionotropic receptors 1 (excitation) Yellow part : passive change in input (glutamate acting on cell)
- Synaptic inputs (graded potential)
Collection of subunits
Beta and gamma – physically bind to receptor for change
- Receptors or TM spanning proteins have highly specific ligand binding domains
that interact to form a pore
Types of neurotransmitters
Small molecule neurotransmitters
o Glutatmate- principle fast excitatory neurotransmitter in mammalian CNS
o Aspartate
o Glycine- inhibitory
o Catecholamines fine tuning/modulatory transmitters
Dopamine, NA, A tyrosine derived
o Indoleamine
Rarely for fast neurotransmission
- Glutamate ionotropic receptors are non-selective cation channels
- 3 families: AMPA, kainate and NMDA
- AMPA, NMDA, Kainate all bind to glutamate name based on another ligand that can also bind to receptor
- One subunit = I gene need at least 4 subunits to make a channel with pore in the middle
- Variations 4 GLU R1 or one of each more than one binding site for glutamate change binding ratio
receptor ligand different variations and affinities
AMPA
o Normal cell- will respond to prolonged explosure ???
o Doesn’t affect ability to bind
- Ligand binding domain interact with M1,M3,M4
- Non-selective for Na+ and K+
o Excitatory more drive for Na+ in than K+ out (already at electrochemical
equilibrium) THUS DEPOLARISE
o Mg2+ is present to block the gate
Gate open to Glutamate but Mg 2+ will still block
Mg2+ removed by depolarisation Mg2+ will move
out as cell is less +ve inside
o Permeable to Ca, Na and K
Drive for Ca and Na but less for K
Increase intracellular Ca (secondary messenger)
o Binding site for glycine
Allosteric modulator here usually inhibitory
transmitter
o activated more slowly wait for depolarisation
Kainate
Glutamate cycle in the neuron
How does the cell differentiate between glutamate (excitatory) and GABA (inhibitory)[ only extra carboxyl group]?
Must fit perfectly within in the binding domain of the
receptor
Glutamine – inactive, floats around in cell and ECF
Glutaminase- convert glutamine to glutamate
Glutamate – from food[protein] high levels in blood after a
meal BBB excludes from brain (protect from excess activity)
VGLUT-Vesicular glutamate transporter (VGLUT-2 common in
brain) must be able to take up glutamate quickly
EATT- excitatory amino acid transporters (fast)
- Reuptake of Glutamate back into the neuron for recycling
and repackaging
- Taken up into Glial cell to break down and release
glutamine back into ECF
Nicotinic acetylcholine receptor
- Ionotropic receptor(ligand-gated )
- 5 subunits and 2 of which are alpha subunits ( pentamers of 4 TM spanning channels)
- Toxins from animals will bind to and inactivate this receptor paralyse you