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Neurophysiology Lecture#3 Date:13/4/2011 In the last lecture we said: The neurotransmitters are divided into two groups: 1) Small molecules rapidly acting neurotransmitters:Which are also subdivided into 4 groups: A) Acetylcholine (ACH) b) Amines Such as epinephrine and norepinephrine which come from tyrosine. c) Amino Acids D) Nitric Oxide Which is a gas and it's a one entity by itself. "Entity= something that has separate and distinct existence" 2) neuropeptides: They are called neuropeptides because almost all of them are peptides. They are also called neuromodulators because they modulate the action of neurotransmitters. They are also subdivided into 4 categories :A) Hypothalamic releasing hormones b) Pituitary peptides ex: β -endorphin c) Peptides that act on gut and brain ex:Leucine Enkephaline ,Methionine Enkephaline(which r one of the opiods* and are pentapeptides) . 4) neuropeptides from other tissues Ex: calcitonin *opiods: are short sequence amino acids that bind to opiod receptors in the brain. Morphine is an example of opiods because it's derived from blank called opium. 1 β-endorphin and Enkephalins are not derived from opium but they have similar action to morphine . That’s why they are called endogenous-opiod neurotransmitters or drugs or called Endogenous –pain suppressor agents. Named Endogenous because they are found in our body. We'll talk about endogenous-opiod neurotransmitters in the next lectures when we come to pain suppression. How we an compare between Small Molecules and Neuropeptides Neurotramsmitters (NT)? 1) Small molecules NT are rapidly acting as compared to slowly acting neuropepides. 2) Small molecules NT have a short lived action compared to prolonged time of action for neuropeptides. "that’s why neuropeptides are needed in some functions that need longer time such as memory and behavior changes" 3) Small molecules NT are excreted in larger amounts compared to smaller quantities of neuropeptide. ((Neuropeptide are excreted in smaller quantities because they are formed in the soma by nissel granules, and it's a very exhausting mechanism of formation, and also their transport through axon by transportal axon is very slow)) 4) Small molecules NT vesicles are recycled but neuropeptide ones are not recycled. *both are found in vesicles. Why are the vesicles of small molecules NT are recycled? 2 Because the enzyme machinery for the formation of small molecules NT is found in the presynaptic vesicle sooo when recycled they can be filled up by the newly formed small molecules NT in the presynaptic terminals. Why are the vesicles of neuropeptides are NOT recycled? Because once the vesicle is fused with the membrane it's going to be part o the membrane. 5) Neuropeptides are co-secreted with small molecules NT to prolong the action of small molecules NT. 6) Neuropeptides are synthesized at the soma while small molecules could be formed at the presynaptic terminals. How are the neurotransmitters removed? 1 * Diffusion: Move down concentration gradient. Ex: ACH diffuses through axons to the interstitial fluid. 2* Enzymatic degradation (breakdown) Examples: a) Neuropeptides will be broken by peptidases or proteases. b) Epinephrine and norepinephrine will be broken by monoamine oxidase. c) ACH is broken down by Acetylcholinesterase Acetylcholine Acetylcholinesterase Choline + acetate To prolong the action ofACH we can give Acetylcholinesterase inhibitor. 3) Some neurotransmitters or the breakdown end products are reuptaken by the presynaptic terminal. 3 Small molecules NT are reuptaken but neuropeptides are not. Ex: Acetylcholine Acetylcholinesterase Choline + acetate Choline is reuptaken to be used again for synthesis of new ACH. General framework of neurotransmitters:- 2)Neuropeptides: are secreted to the cleft. They can be broken by peptidases or proteases. As u can c here they're NOT reuptaken. 1) Small molecules NT: Are found within vesicles and are released by exocytosis as you can see. ACH is an example; it can be brokendown, and choline is reuptaken 3) Gaseous: Ex: Nitric oxide. It has NO receptor because the gas is lipid soluble and goes out of the presynaptic vesicle to enter post synaptic neuron and activates a variety of enzymes "for ex: it can change the metabolism of a cell by changing the activity of certain enzyme. Receptors: * Are located at postsynaptic membrane *they could be coupled to ion channels "ionophores". * they could be coupled to neighboring enzymes such as "adlynl cyclase , phospholipase c" to end in the formation of secondary messenger which has a prolonged mechanism. 4 *In the axon hellox the density of voltage gated Na+ channels is more than any other place in the neuron. In dendrites there are variable or even NO voltage gated Na+ channels are found. Resting membrane potential= Results from the distribution of ions across the neuronal membrane ((it's a result of the concentatiom of the following ions " Na+ , K+ , Cl– and sometimes Ca++ " )) We can calculate the resting membrane potential by Goldman's Hodgkin-Katz equation, taking in consideration the permeability and concentration of ions inside and outside. Resting membrane potential ~ -65 mV by Goldman's Hodgkin-Katz equation. But what's important for us is to calculate the equilibrium potential by using Nernst equation, supposing that the ion that we are calculating the equilibrium potential for it is only ion found in the cell. Nernst Potential:Potential that exactly opposes the movement of an ion across the neuronal membrane. Nernst Equation: Electro Motive Force (EMF) (mV) EMF (mV) 61 log conc. inside conc. otside *The sign is (-) for a positive ion and (+) for a negative ion. 5 Examples: Calculate the Electro Motive Force (EMF) for Na+ ?? We know that the concentration of Na+ outside is ~140 the concentration of Na+ inside is ~14 Then -61 log 14 140 =-61 log 0.1 = -61*-1 = 61(mV) **now A neurotransmitter is released, it binds its receptor, the receptor is coupled to a cationic or anionic channels. If this cationic channel is (Na+ ) then(Na+ ) will enter the cell from extracellular fluid according to electrochemical gradient. Soooo (Na+ ) will try to reach its equilibrium potential and make the potential of the cell +61. But this will NEVER be reached, because once it (Na+ ) enters it'll change the membrane permeability to other ions. For ex: entry of Na+ will cause the exit of K+. This change in the membrane permeability in the postsynaptic neuron is called DEPOLARIZING POTENTIAL. In this case the membrane potential has changed for ex: from (-70)mv – (-50)mv So the membrane potential change is 20 (mv) sooo the negativity of the membrane has decreased. DEPOLARIZING POTENTIAL = excitatory postsynaptic potential. "Excitatory" because it's coming closer to the threshold. "Postsynaptic" because it occurs in the postsynaptic membrane. 6 Characteristics of excitatory postsynaptic potential (EPSP0:1♦ Depolarizing Potential 2♦ local potential:In contrast to action potential which is NOT local but rather it spreads "conducted" very fast through the axon. summation Threshold EPSP 3♦ Graded: If a second stimulus occurs after the first stimulus it'll add to the potential. ((graded=can be summated)) * The action potential can't be summated because it follows the All OR NONE PRICIPLE. 4♦ prolonged duration. Q: How much time we need to form (or have) EPSP? 1-2 milliseconds, and it stays longer than action potential. It stays 15-20 milliseconds. Meaning that it has a prolonged duration. While the action occurs every 0.1 millisecond **This Characteristic is important because if EPSP reached the threshold and its duration as we know 15-20 milliseconds then during this time we'll have more than one action potential happening. Q: What is the rate of action potential/sc? Each action potential takes 0.1 millisecond. 1 second=1000 millisecond Rate =1000 = 1000 1 7 As u can c that EPSP might or might not rech Threshold Q:if the action potential occurs every 0.8 millisecond then what's the discharge rate? 1000 0.8 = 1250 The action potential rate has other names like: Firing rate, discharge rate, impulse rate. Q:Can we increase the rate of firing? ● Yes we can by increasing the strength of the stimulus. If the stimulus is much more above threshold then we can stimulate the neuron during relative refractory period (RRP) * As we know that the absolute refractory period (ARP)is half the repolarizing phase and we can't stimulate the neuron whatever the strength of the stimulus is. RRP ARP As u see that the rate is increased for ex: action potential is happening every 0.8 milliseconds ●The rate is increased by increasing the amplitude of EPSP and by increasing the # of neurotransmitters. Amplitude 40 (mv) Amplitude 30 mv 8 so the rate increased ** If the neurotransmitters is coupled to a receptor which will open anionic channels (Cl–) or cationic channel (K+ ) then we'll have the membrane potential more negative ((away from the threshold )). This is the Inhibitory postsynaptic potential (IPSP). * IPSP has the same characteristics as EPSP Note: Depolarizing potential Repolarizing potential ●Is excitatory ● is inhibitory ●EPSP increases the permeability of the membrane to (Na+ ) ● IPSP increases the permeability of the membrane to (K+ ) ●EPSP makes the membrane less Negative. ● IPSP Makes the membrane more Negative. Note before:(Cl–) => Might not change the potential of the membrane, but it has an inhibitory effect. This inhibitory action is called "short cut inhibition" by increasing the permeability to (Cl–) channels. 9 Q:What determines the action of neurotransmitters if it's an inhibitory or stimulatory effect?? The receptor and to what it's coupled to. Ex: If The receptor is coupled to cationic channel (K+ ) (inhibitory) If The receptor is coupled to cationic channel (Na+ ) (stimulatory) Another example: ACH in the heart has an inhibitor effect. Because the sympathetic causes decrease in the heart rate. While ACH in the GI causes increase in the secretion and movement. So you can notice that the same neurotransmitters in one area worked as stimulatory while in other area it worked as an inhibitory. By: Lara al -Lahham 10