What does hyperpolarisation mean in terms of excitability of a neuron?
-after firing an AP, the membrane is hyperpolarised and is harder to excite another AP than at resting membrane potential
-less receptive to another excitatory input
What is the principle inhibitory neurotransmitter?
What is the GABA system like?
- GABA is manufactured in glucose metabolism which is converted to Glutamate
-Glutamate is converted into GABA via the Glutamic acid decarboxylase+ pyroxidal phosphate -GABA is then packagedinto vesicles by a specific transporter the VIATT
-then when the cell is depolarised get a spike in Calcium and the GABA containing vesicles are released into the synaptic cleft -GABA binds (mainly to ionotropic receptors)
-GABA is then taken into the glial cells or back into the presynaptic terminal via the transporter GAT
-GABA can be then packaged again as GABA or can used in the glucose metabolism, where it is broken down into glucose (GABA can also be made from pyruvate)
What is the Glycine system like?
-another inhibitory neurotransmitter -also a result of glucose metabolism, glucose into serine
-serine is made into Glycine via the serine transhydroxy-methylase
-Glycine is then packaged into vesicles via the VIATT
-then calcium dependent release and then taken up by the glycine transporter, recycled
What are the different functions of Glycine and GABA?
-GABA is more in the brain, Glycine is more from medulla down, important in the spinal cord -generalisation!
How do the glycine and GABA receptors compare?
-receptors are similar but different subunits both are pentamers
-GABA is made up of combination of alpha, beta, gamma, etc.,most common configuration is 1 alpha, 2 beta and 2 gamma = a pentamer
-that is the most common GABAaR in brain (the alpha1beta2gamma2 complex)
-selectivity for Cl-
-modulated by picrotoxin and barbituates (bind that molecule and modulate the function of the GABA receptors) lot of anesthetics work by altering the function of GABA receptors
What is this?
-GABA inhibits the cell -how does opening of Cl channel change the behaviour of a tonically active neuron?
What determines the movement of an ion through an ion channel and the direction of the movement?
-concentrations of the ions in and out of the membrane -equilibrium potentials -Cl= 150 mM outside and 13mM inside= -65 is the equilibrium potential -what happens to Cl when open the channel and why does that inhibit the channel? -Cl eq. Is the same as membrane potential
What is this?
-Goldmann equation -used in cell membrane physiology to determine the reversal potential across a cell's membrane, taking into account all of the ions that are permeant through that membrane
-calculating the resting membrane potential
-R=gas constant Nernst equation
-F=Faraday’s constant (charge per mole of ion)
-P(ion)= permeability to that ion, 1 is when the membrane represents no barrier to movement and 0 when the membrane is a perfect barrier to movement (we do not ever get this in an evolved biological system)
What is this?
What is the Vm (resting membrane potential) if PK=1 and PNa=0?
-at 37C -RT=61 -This is the membrane potential is the cell perfectly permeable to K+ with the known intra- and extra-cellular K+ concentrations.
-Why then do we always see the resting membrane potential = -65 mV? -because : When K+ is the determining factor -biology, always more factors, PK is almost 1 but almost, Pna is not 0 but almost (as always a leakage into the cell)
What happens if we close the K+ channels and open the Na+ channels (PK=0 and PNa=1)
-if the cell only permeable to Na = the cell would want to be at +61 -that is what happens when the hyperpolarisation, tendency towards it but in reality there is more fatcors like Ca2+ etc.
What if we close the K+ channels and open the Cl- channels? PK = 0 and PCl = 1
-opening a Cl channel at rest should do very little, so why is it a principle inhibitory transmitter does that? - the e gradient acting on movement of Cl will change as the cell becomes depolarised= the interior of the cell will become more positive= to chloride that is negative the chloride is attracted to the positivity
-the Cl will make the cell more negative
-the more positive the cell (the drive) the more drive to Cl to come in and negativise
-same in the opposite direction when negativsiation will repel the Cl
-it is not the channel that determines where the ion goes, it is the electrical gradients that do, the channel is just a hole, it is the chemical and electrical gradient that determines the effect of a neurotransmitter
What is the difference in the matured and developing brain in terms of GABA function?
-in a maturing brain the membrane potential determined differently
-opening a GABA receptor in an immature neuron is an excitatory neurotransmitters
-adult gut GABA is excitatory!!!
-it is not the GABA nor the channel but the drive
-in immature neurons Cl is much higher in the neuron
-the cotransporter responsible Na K 2 Cl= then gets downregulated as you age and changes into K+ Cl- cotransporter
-it is thought that a delay in the switch is maybe causative in autism
-purple square= concentration of Cl in age in days
-then pictures of chloride concentration in neurons at 5 10 and 20, decrease
What is the GABA ion channel linked to?
-the GABA ion channel is intimately linked with diseases like epilepsy
-4 membrane spanning domains -the colour dots (point mutations) that are detected in families with particular types of epileps
- beta3- childhood epilepsy
-GABA receptor maintaining inhibitory tone, and maintaing excitability at the right level is incredibly importnat
-not involved in postsynaptic, outside the synapse= setting the excitability, so any input has more efefct (look at which gene)!
What is the connection of GABA and epilepsy?
-Mutations in γ2 and α1 subunits identified.
• Fast inhibitory membrane potential changes involve hyperpolarization, or shunting. • Open channels that allow increased movement of potassium (out) will make the interior of the cell more negative ‐ hyperpolarisation. • Chloride ion channels retain the membrane potential approximately at RMP and shunt excitatory inputs. • GABA and glycine are the major inhibitory transmitters of the mammalian CNS. • Nernst potentials describe the point of equilibrium for movement of a given ion through an open channel. Determined largely by ion concentrations. • The equilibrium potential provides an idea of the reversal potential. • GABA is very important for maintaining the stability of brain function.
• Fast transmitters are recycled within the region of the synaptic terminal. • Ion channels are not directional–the direction of movement of an ion will be determined by the driving forces – chemical and electrical gradients. • These are described by the Nernst equation and the reversal potential. • Hence the same ion channel (GABA ion channel) can be inhibitory or excitatory.