PSL300 Lecture Notes PDF

PSL300 PSL300 - Lecture 04 Post-Synaptic Receptors – Ionotropic Receptors – Metabotropic Receptors Spread of PSP PSP Summation – Spatial Summation – Temporal Summation Inhibitory Synaptic Potential AP Spike Train Transmitter Removal Post Synaptic Rec...

PSL300 PSL300 - Lecture 04 Post-Synaptic Receptors – Ionotropic Receptors – Metabotropic Receptors Spread of PSP PSP Summation – Spatial Summation – Temporal Summation Inhibitory Synaptic Potential AP Spike Train Transmitter Removal Post Synaptic Receptors Transmitter agent diffuses across synapse and binds to a specific site on a receptor protein embedded in postsynaptic membrane Binding of transmitter causes a change in shape of the receptor protein Receptors are either – Ionotropic (directly opens channels) – Metabotropic (initiates a metabolistic cascade to activate enzymes) Receptor determines the effect, not the transmitter Ionotropic Effects Ligand binding opens an ion channel > Ionotropic Binding of the transmitter to the post-synaptic membrane results in change in the post-synaptic membrane potential, this is called the Post-Synaptic Potential (PSP) The duration of PSP is about 20-40 ms (as long as the transmitters are present) Ion channel may be specific for cations (Na+, K+) > EPSP (depolarizing) Or ion channel may be specific for Cl- or K+ ion > IPSP (hyperpolarizing) Ionotropic Effects Nicotinic receptor for Acetylcholine Ionotropic Effects Nicotinic receptor for Acetylcholine Ligands for Ionotropic Receptors The ligands for the ionotropic receptors (transmitters that can act on ionotropic receptors) are principally: – Acetylcholine (Ach) – Glutamate – GABA – Glycine All these ligands can act on the metabotropic receptors; It’s the receptor that determines the effect and not the transmitter Ligands for Ionotropic Receptors The ligands for the ionotropic receptors (transmitters that can act on ionotropic receptors) are principally: – Acetylcholine (Ach) – Glutamate – GABA – Glycine All these ligands can act on the metabotropic receptors; It’s the receptor that determines the effect and not the transmitter Metabotropic Effects Binding of the ligand to the post-synaptic metabotropic receptor activates an enzyme that is usually G-protein coupled The enzyme facilitation will result in  (production) or destruction of 2nd messengers 2nd messengers are either cAMP, cGMP, or InP3 2nd messenger then activates other enzymes, e.g. phosphokinases which phosphorylate membrane proteins or other proteins in the cytoplasm If you phosphorylate membrane proteins (i.e. ion channels) > result in modulation of ion currents Metabotropic Effects Binding of the ligand to the post-synaptic metabotropic receptor activates an enzyme that is usually G-protein coupled The enzyme facilitation will result in  (production) or destruction of 2nd messengers 2nd messengers are either cAMP, cGMP, or InP3 2nd messenger then activates other enzymes, e.g. phosphokinases which phosphorylate membrane proteins or other proteins in the cytoplasm If you phosphorylate membrane proteins (i.e. ion channels) > result in modulation of ion currents Metabotropic Effects Ionotropic effect is much more immediate (opens ion channel directly) The metabotropic receptor activation takes time Moreover, it is not necessary that there is any change in the MP, it might be all internal metabolic effect But if you influence an ion channel through the metabolic effect (i.e. through phosphorylation), the change in MP will develop slowly (slow EPSP, slow IPSP) Change is slow because of it has to go through all the enzyme activity first before influencing the ion channels -Adrenoreceptor  -receptor is a metabolic receptor for Noradrenalin (NA) Binding of NA to  -receptor activates adenylyl cyclase via G-protein alteration adenylyl cyclase  production of cAMP (2nd messenger) cAMP then activates kinases which phosphorylate membrane Ca++ channel This phosphorylation of the Ca++ channel > increase in Ca++ influx (important in heart muscle, increases contractility) Beta-blockers -Adrenoreceptor  -receptor is a metabolic receptor for Noradrenalin (NA) Binding of NA to  -receptor activates adenylyl cyclase via G-protein alteration adenylyl cyclase  production of cAMP (2nd messenger) cAMP then activates kinases which phosphorylate membrane Ca++ channel This phosphorylation of the Ca++ channel > increase in Ca++ influx (important in heart muscle, increases contractility) Beta-blockers Ligands for Metabotropic Receptors ACh: Muscarinic receptor Peptides: substance P,  -endorphin, ADH Catecholamines: noradrenaline, dopamine Serotonin Purines: adenosine, ATP Gases: NO, CO Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs Nearest excitable membrane is at the beginning of the axon > trigger zone Spread of PSPs Binding of transmitter > generates PSP PSPs must spread through passive conduction across the membrane to get to the initial segment of the axon Trigger zone PSP Summations Biological tissues have poor cable property (compared to telephone cables) Thus, there will be loss of current (potential) as you go along the membrane before reaching the trigger zone PSP Summations Biological tissues have poor cable property (compared to telephone cables) Thus, there will be loss of current (potential) as you go along the membrane before reaching the trigger zone Types of PSP Summations What are the 2 types of Summation that occur? – Spatial summation: minimum of 10-30 synchronous EPSPs in dendritic tree, each generated at a different synapse – Temporal summation: only a few active synapses, but each generating EPSPs at high frequency; summated potentials reach threshold over a period of time Spatial Summation Spatial summation: Large number of EPSPs in synchrony Spatial Summation Spatial summation: Large number of EPSPs in synchrony Temporal Summation Temporal summation: EPSPs last for about 30-40 ms in duration before dying out, thus, successive inputs on any given synapse generates subsequent EPSPs that add on to pre-existing EPSPs (e.g. 10 ms apart) Summation causing action potential. If two subthreshold potentials arrive at the trigger zone within a short period of time, Stimuli they may sum and initiate an action potential. (X1 & X2) 30 0 Membrane potential (mV) 55 Threshold A2 A1 70 X1 X2 Time (msec) Temporal Summation Temporal summation: EPSPs last for about 30-40 ms in duration before dying out, thus, successive inputs on any given synapse generates subsequent EPSPs that add on to pre-existing EPSPs (e.g. 10 ms apart) Summation causing action potential. If two subthreshold potentials arrive at the trigger zone within a short period of time, Stimuli they may sum and initiate an action potential. (X1 & X2) 30 0 Membrane potential (mV) 55 Threshold A2 A1 70 X1 X2 Time (msec) Inhibitory Post-Synaptic Potential IPSPs tend to be preferentially located on the cell soma, interposed ½ way between the site where EPSP is generated and the trigger zone IPSPs have strategic advantage: due to its location close to the trigger zone > can shunt depolarizing EPSP currents out of cell Inhibitory Post-Synaptic Potential IPSPs located on the cell soma (½ way between the site where EPSP is generated and the trigger zone) can shunt depolarizing EPSP currents out of cell How can IPSPs shunt depolarizing EPSP currents? X IPSP (Cl- Channel) IPSP involves the opening of the Cl- channel The equilibrium potential for Cl- is very close to the resting MP (-70 mV) Therefore at rest, opening of the Cl- channel would result in little change However, when the membrane is depolarized, opening of the Cl- channel will bring the MP back down to -70 mV The net affect of Cl- is basically to ‘clamp’ the MP, which is preventing excitation, thus preventing depolarization > inhibitory effect These IPSPs are very strategically located and they completely block any signal coming from EPSPs simply by positioning right on the soma IPSPs IPSPs in general in the Nervous System, are more important than EPSPs Generating a Spike Train It’s easy to see that when summated EPSPs arrive at the trigger zone, it achieve threshold and an AP (spike) is triggered But what happens when you have a very powerful synaptic input to the post- synaptic neuron persisting in time lasting up to 500 ms? Depolarizing the trigger zone to threshold and sustain that depolarization for 500 ms, you want that powerful input to be translated into continuous stream of APs > This is called the ‘Spike Train’ Generating a Spike Train If we depolarize the membrane above threshold and keep it there, you’ll get one AP and the voltage-gated Na+ channels will inactivate (refractory period) and you can not get another AP until the membrane repolarizes Therefore, after each ‘spike’ we need to get the membrane ‘hyperpolarized’ to restore the Na+ channels to re-open them for the next one We must have Hyperpolarization to generate another AP, otherwise we’ll never generate a ‘Spike Train’ Generating a Spike Train The idea is to overcome the depolarization ‘block’ 500 ms Generating a Spike Train The idea is to overcome the depolarization ‘block’ 500 ms After-Hyperpolarization Voltage-gated K+ channels at trigger zone cause afterhyperpolarizations Hyperpolarization after each spike ensures that Na+ channels reconfigure, and membrane excitability is restored After the hyperpolarization fades away (voltage-gated K+ channels will close when the membrane is repolarized), the MP will be able to shoot right back up where EPSP is taking it and cross the threshold again and a whole new spike and this will repeat until the EPSP fades away Thanks to afterhyperpolarization we could generate a ‘Spike Train' Thank You!