Lecture 4- Ionotropic receptors II: Inhibition Flashcards Preview

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Flashcards in Lecture 4- Ionotropic receptors II: Inhibition Deck (18):
1

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

2

What is the principle inhibitory neurotransmitter?

-GABA

3

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)

4

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

5

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!

6

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

7

What is this?

-GABA inhibits the cell -how does opening of Cl channel change the behaviour of a tonically active neuron?

8

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

9

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

-T=temperature (absolute)

-z=valence (charge)

-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)

10

What is this?

-Nernst equation

11

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)

12

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.

13

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

-shunting

-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

14

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

15

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)!

16

What is the connection of GABA and epilepsy?

-Mutations in γ2 and α1 subunits identified.

17

Summary:

• 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.

18

Core concepts?

• 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.