Signal Transmission Between the Neurons 1 Neurotransmission 1.Chemical synapse (Classical Synapse) – Predominates in the vertebrate nervous system 2. Non-synaptic chemical transmission 3. Electrical synapse – Via specialized gap junctions – Does occur, but rare in vertebrate NS – Astrocytes can communicate via gap junctions 2 Chemical Synapse • Terminal bouton is separated from postsynaptic cell by synaptic cleft. • Vesicles fuse with axon membrane and NT released by exocytosis. • Amount of NTs released depends upon frequency of AP. 3 Non-synaptic chemical transmission The postganglionic neurons innervate the smooth muscles. No recognizable endplates or other postsynaptic specializations; The multiple branches are beaded with enlargements (varicosities) that are not covered by Schwann cells and contain synaptic vesicles; Fig. : Ending of postganglionic autonomic neurons on smooth muscle 4 Non-synaptic chemical transmission continued In noradrenergic neurons, the varicosities are about 5 m, with up to 20,000 varicosities per neuron; Transmitter is apparently released at each varicosity, at many locations along each axon; One neuron innervate many effector cells. Fig. : Ending of postganglionic autonomic neurons on smooth 5 muscle Electrical Synapse • Impulses can be regenerated without interruption in adjacent cells. • Gap junctions: – Adjacent cells electrically coupled through a channel. – Each gap junction is composed of 12 connexin proteins. • Examples: – Smooth and cardiac muscles, brain, and glial cells. 6 Electrical Synapses •Electric current flowcommunication takes place by flow of electric current directly from one neuron to the other •No synaptic cleft or vesicles cell membranes in direct contact •Communication not polarized- electric current can flow between cells in either direction 7 Electrical Synapse Chemical Synapse Purves, 28001 I The Chemical Synapse and Signal Transmission 9 • The chemical synapse is a specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes 10 Synaptic connections • ~100,000,000,000 neurons in human brain • Each neuron contacts ~1000 cells • Forms ~10,000 connections/cell • How many synapses? 11 •Neurotransmittercommunication via a chemical intermediary Chemical Synapses called a neurotransmitter, released from one neuron and influences another •Synaptic cleft- a small gap between the sending (presynaptic) and the receiving (postsynaptic) site 12 •Synaptic vesiclessmall spherical or oval Chemical Synapses organelles contain chemical transmitter used in transmission •Polarizationcommunication occurs in only one direction, from sending presynaptic site, to receiving postsynaptic site 13 1. Synaptic Transmission Model • • • • • • Precursor transport NT synthesis Storage Release Activation Termination ~diffusion, degradation, uptake, autoreceptors 14 Presynaptic Axon Terminal Terminal Button Postsynaptic Membrane Dendritic Spine 15 (1) Precursor Transport 16 (2) Synthesis _ _ _ enzymes/cofactors NT 17 (3) Storage in vesicles 18 NT Terminal Button Dendritic Spine Synapse Vesicles 19 (4) Release Terminal Button Dendritic Spine Synapse Receptors 20 Terminal Button AP Dendritic Spine Synapse 21 Exocytosis Ca2+ 22 Each vesicle contains one quanta of neurotransmitter (approximately 5000 molecules) – quanta release 23 (5) Activation 24 (6) Termination 25 (6.1) Termination by... Diffusion 26 (6.2) Termination by... Enzymatic degradation 27 (6.3) Termination by... Reuptake 28 (6.4) Termination by... Autoreceptors A 29 Autoreceptors • On presynaptic terminal • Binds NT same as postsynaptic receptors different receptor subtype • Decreases NT release & synthesis • Metabotropic receptors 30 Synaptic Transmission • AP travels down axon to bouton. • VG Ca2+ channels open. – Ca2+ enters bouton down concentration gradient. – Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs. • Ca2+ activates calmodulin, which activates protein kinase. • Protein kinase phosphorylates synapsins. – Synapsins aid in the fusion of synaptic vesicles. 31 Synaptic Transmission (continued) • NTs are released and diffuse across synaptic cleft. • NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane. • Chemically-regulated gated ion channels open. – EPSP: depolarization. – IPSP: hyperpolarization. • Neurotransmitter inactivated to end transmission. 32 2 EPSP and IPSP 33 (1)Excitatory postsynaptic potential (EPSP) AnAP arriving in the presynaptic terminal cause the release of neurotransmitter; The molecules bind and active receptor on the postsynaptic membrane; 34 (1)Excitatory postsynaptic potential (EPSP) Opening transmittergated ions channels ( Na+) in postsynapticmembrane; Both an electrical and a concentration gradient driving Na+ into the cell; Thepostsynaptic membrane will become depolarized(EPSP). 35 • No threshold. • Decreases resting membrane potential. EPSP – Closer to threshold. • Graded in magnitude. • Have no refractory period. • Can summate. 36 (2) Inhibitory postsynaptic potential (IPSP) •A impulse arriving in the presynaptic terminal causes the release of neurotransmitter; •The molecular bind and active receptors on the postsynaptic membrane open CI- or, sometimes K+ channels; •More CI- enters, K+ outer the cell, producing a hyperpolarization in the postsynaptic membrane. 37 •(IPSPs): –No threshold. –Hyperpolarize postsynaptic membrane. –Increase membrane potential. –Can summate. –No refractory period. 38 39 3 Synaptic Inhibition • Presynaptic inhibition: – Amount of excitatory NT released is decreased by effects of second neuron, whose axon makes synapses with first neuron’s axon. • Postsynaptic inhibition 40 (1) Postsynaptic inhibition Concept: effect of inhibitory synapses on the postsynaptic membrane. Mechanism: IPSP, inhibitory interneuron Types: Afferent collateral inhibition( reciprocal inhibition) Recurrent inhibition. 41 1) Reciprocal inhibition Postsynaptic inhibition Activity in the afferent fibers from the muscle spindles (stretch receptors) excites (EPSPs) directly the motor neurons supplying the muscle from which the impulses come. At the same time, inhibits (ISPSs) those motor neurons supplying its antagonistic muscles. 42 1) Reciprocal inhibition Postsynaptic inhibition The latter response is mediated by branches of the afferent fibers that end on the interneurons. The interneurons, in turn, secrete the inhibitory transmitter (IPSP) at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist. 43 Neurons may also inhibit Postsynaptic themselves in a negative feedback fashion. inhibition 2) Recurrent inhibition Each spinal motor neuron regularly gives off a recurrent collateral that synapses with an inhibitory interneuron which terminates on the cell body of the spinal neuron and other spinal motor neurons. The inhibitory interneuron to secrete inhibitory mediator, slows and stops the discharge of the motor neuron. 44 Concept: the inhibition occurs at the presynaptic terminals before the signal ever reaches the synapse. The basic structure: an axon-axon synapse (presynaptic synapse), A and B. Neuron A has no direct effect on neuron C, but it exert a Presynaptic effect on ability of B to Influence C. The presynatic effect May decrease the amount of neuro- transmitter released from B (Presynaptic inhibition) or increase it (presynaptic facilitation). (2) Presynaptic inhibition AA B A B C C 45 Presynaptic inhibition The mechanisms: • Activation of the presynaptic receptors increases CIconductance, to decrease the size of the AP reaching the excitatory ending, reduces Ca2+ entry and consequently the amount of excitatory transmitter decreased. •Voltage-gated K+ channels are also opened, and the resulting K+ efflux also decreases the Ca2+ influx.46 Presynaptic Inhibition Excitatory Synapse A + B • A active • B more likely to fire • Add a 3ะก neuron ~ 47 Presynaptic Inhibition Excitatory Synapse A - + B C • Axon-axon synapse • C is inhibitory ~ 48 Presynaptic Inhibition Excitatory Synapse A - + B C • C active • less NT from A when active • B less likely to fire ~ 49 4 Synaptic Facilitation: Presynaptic and Postsynaptic 50 (1) Presynaptic Facilitation Excitatory Synapse A + B • A active • B more likely to fire ~ 51 Presynaptic Facilitation Excitatory Synapse A + C + B • C active (excitatory) • more NT from A when active (Mechanism:AP of A is prolonged and Ca 2+ channels are open for a longer period.) • B more likely to fire ~ 52 (2) Postsynaptic facilitation: neuron that has been partially depolarized is more likely to make AP. 53 Record here EPSP + + • Depolarization more likely to fire ~ Vm -65mv - 70mv AT REST Time 54 • EPSPs can summate, producing AP. – Spatial summation: 5 Synaptic Integration • Numerous PSP converge on a single postsynaptic neuron (distance). – Temporal summation: • Successive waves of neurotransmitter release (time). 55 (1) Spatial Summation • The accumulation of neurotransmitter in the synapse due the combined activity of several presynaptic neurons entering the Area (Space) of a Convergent Synapse. • A space (spatial) dependent process. 56 Spatial Summation + + + • Multiple synapses vm -65mv - 70mv AT REST Time 57 (2) Temporal Summation • The accumulation of neurotransmitters in a synapse due to the rapid activity of a presynaptic neuron over a given Time period. • Occurs in a Divergent Synapse. (explain later) • Is a Time (Temporal) dependent process. 58 Temporal Summation + + Repeated stimulation same synapse ~ Vm -65mv - 70mv resting potential Time 59 (3) EPSPs & IPSPs summate • CANCEL EACH OTHER • Net stimulation – EPSPs + IPSPs = net effects ~ 60 EPSP + IPSP + - 70mv - 61 6. Divergent and Convergent Synapse 62 Divergent Synapse •A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons (ratio of pre to post is less than one). •The stimulation of the postsynaptic neurons depends on temporal summation. 63 Convergent Synapse •A junction between two or more presynaptic neurons Presynaptic neurons with a postsynaptic neuron (the ratio of pre to post is greater than one). •The stimulation of the postsynaptic neuron depends on the Spatial Summation. Postsynaptic neuron 64 II Neurotransmitters and receptors 65 1. Basic Concepts of NT and receptor Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells. Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells 66 •Vast array of molecules serve as neurotransmitters •The properties of the transmitter do not determine its effects on the postsynaptic cells •The properties of the receptor determine whether a transmitter is excitatory or inhibitory 67 A neurotransmitter must (classical definition) • • • • • Be synthesized and released from neurons Be found at the presynaptic terminal Have same effect on target cell when applied externally Be blocked by same drugs that block synaptic transmission Be removed in a specific way Purves, 200168 Classical Transmitters (small-molecule transmitters) •Biogenic Amines •Acetylcholine •Catecholamines •Dopamine •Norepinerphrine •Epinephrine •Serotonin •Amino Acids Non-classical Transmitters •Neuropeptides •Neurotrophins •Gaseous messengers –Nitric oxide –Carbon Monoxide •D-serine •Glutamate •GABA ( -amino butyric acid) •Glycine 69 Agonist A substance that mimics a specific neurotransmitter, is able to attach to that neurotransmitter's receptor and thereby produces the same action that the neurotransmitter usually produces. Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted. 70 Antagonist Drugs that bind to but do not activate neuroreceptors, thereby blocking the actions of neurotransmitters or the neuroreceptor agonists. 71 • Same NT can bind to different -R • different part of NT ~ Receptor A NT NT Receptor B 72 Specificity of drugs Drug A Receptor A Drug B NT Receptor B 73 Five key steps in neurotransmission • Synthesis • Storage • Release • Receptor Binding • Inactivation Purves7,42001 Synaptic vesicles • Concentrate and protect transmitter • Can be docked at active zone • Differ for classical transmitters (small, clear-core) vs. neuropeptides (large, dense-core) 75 Neurotransmitter Co-existence (Dale principle all the secretions of one neuron secrete the same mediator, 1935) Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter. They are contained in different synaptic vesicles that can be distinguished using the electron microscope. The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions. 76 Purves, 270701 Receptors determine whether: • Synapse is excitatory or inhibitory – NE is excitatory at some synapses, inhibitory at others • Transmitter binding activates ion channel directly or indirectly. – Directly • ionotropic receptors • fast – Indirectly • metabotropic receptors • G-protein coupled • slow 78 2. Receptor Activation • Ionotropic channel – Receptor directly controls channel – fast • Metabotropic channel – second messenger systems – receptor indirectly controls channel ~ 79 (1) Ionotropic Channels Channel NT neurotransmitter 80 Ionotropic Channels NT Pore 81 Ionotropic Channels NT 82 Ionotropic Channels 83 (2) Metabotropic Channels • Receptor separate from channel • G proteins • 2d messenger system – cAMP – other types • Effects – Control channel – Alter properties of receptors – regulation of gene expression ~ 84 (2.1) G protein: direct control • NT is 1st messenger • G protein binds to channel – opens or closes – relatively fast ~ 85 G protein: direct control R G GDP 86 G protein: direct control R G GTP Pore 87 (2.2) G protein: Protein Phosphorylation external external signal: signal: NT nt norepinephrine Receptor Receptor b adrenergic -R transducer primary effector GS adenylyl cyclase 2d messenger cAMP secondary effector protein kinase 88 G protein: Protein Phosphorylation A C R G GDP PK 89 G protein: Protein Phosphorylation A C R G ATP GTP cAMP PK 90 G protein: Protein Phosphorylation A C R G ATP GTP P cAMP PK Pore 91 (3) Transmitter Inactivation • • • • • • Reuptake by presynaptic terminal Uptake by glial cells Enzymatic degradation Presynaptic receptor Diffusion Combination of above 92 Summary of Synaptic Transmission Purves,200931 Basic Neurochemi9s4try 3. Some Important Transmitters 95 (1) Acetylcholine (ACh) as NT 96 Acetylcholine Synthesis choline acetyltransferase choline + acetyl CoA ACh + CoA 97 Acetylcholinesterase (AChE) • Enzyme that inactivates ACh. – Present on postsynaptic membrane or immediately outside the membrane. • Prevents continued stimulation. 98 99 The Life Cycle of Ach 100 Ach - Distribution • Peripheral N.S. • Excites somatic skeletal muscle (neuro-muscular junction) • Autonomic NS Ganglia Parasympathetic NS--- Neuroeffector junction Few sympathetic NS – Neuroeffector junction • Central N.S. - widespread Hippocampus Hypothalamus ~ 101 ACH Receptors •ACh is both an excitatory and inhibitory NT, depending on organ involved. –Causes the opening of chemical gated ion channels. •Nicotinic ACh receptors: –Found in autonomic ganglia (N1) and skeletal muscle fibers (N2). •Muscarinic ACh receptors: –Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands . 102 Acetylcholine Neurotransmission • “Nicotinic” subtype Receptor: – Membrane Channel for Na+ and K+ – Opens on ligand binding – Depolarization of target (neuron, muscle) – Stimulated by Nicotine, etc. – Blocked by Curare, etc. – Motor endplate (somatic) (N2), – all autonomic ganglia, hormone producing cells of adrenal medulla (N1) 103 Acetylcholine Neurotransmission • “Muscarinic” subtype Receptor: M1 – Use of signal transduction system • Phospholipase C, IP , Diacylglycerol DAG, 3 – – – – cytosolic Ca++ Effect on target: cell specific ( smooth muscle intestine ) Blocked by Atropine, etc. All parasympathetic target organs Some sympathetic targets (exocrine sweat glands, skeletal muscle blood vessels - dilation) 104 Acetylcholine Neurotransmission • “Muscarinic” subtype: M2 – Use of signal transduction system • via G-proteins, opens K+ channels, decrease in cAMP levels – Effect on target: cell specific (heart ) – CNS – Stimulated by ? – Blocked by Atropine, etc. 105 Cholinergic Agonists • Direct – Muscarine – Nicotine • Indirect – Acetylcholinesterase inhibitors (ACH is not eliminated by ACHe) 106 Cholinergic Antagonists • Direct Nicotinic – Curare and Curarelike drugs Muscarinic – Atropine •Indirect- ACHe (ACH is eliminated by ACHe) 107 Ligand-Operated ACh Channels N Receptor 109 M receptor G Protein-Operated ACh Channel 110 (2) Monoamines as NT 111 Monoamines • Catecholamines – Dopamine - DA Norepinephrine - NE Epinephrine - E • Indolamines Serotonin - 5-HT 112 Mechanism of Action ( receptor) 113 Epi 1 G protein PLC IP3 Ca+2 114 Norepinephrine (NE) as NT • NT in both PNS and CNS. • PNS: – Smooth muscles, cardiac muscle and glands. • Increase in blood pressure, constriction of arteries. • CNS: – General behavior. 115 116 Adrenergic Neurotransmission 1 Receptor – Stimulated by NE, E, – blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary glands – vasoconstriction, sphincter constriction, pupil dilation 117 Adrenergic Neurotransmission 2 Receptor – stimulated by, NE, E, ….. – Membrane of adrenergic axon terminals (presynaptic receptors), platelets – inhibition of NE release (autoreceptor), – promotes blood clotting, pancreas decreased insulin secretion 118 Adrenergic Neurotransmission • 1 receptor – stimulated by E, …. – Mainly heart muscle cells, – increased heart rate and strength 119 Adrenergic Neurotransmission • 2 receptor – stimulated by E .. – Lungs, most other sympathetic organs, blood vessels serving the heart (coronary vessels), – dilation of bronchioles & blood vessels (coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus 120 Adrenergic Neurotransmission • 3 receptor – stimulated by E, …. – Adipose tissue, – stimulation of lipolysis 121 (3) Amino Acids as NT • Glutamate acid and aspartate acid: – Excitatory Amino Acid (EAA) • gamma-amino-butyric acid (GABA) and glycine: – Inhibitory (IAA) 122 (4) Polypeptides as NT • CCK: – Promote satiety following meals. • Substance P: – Major NT in sensations of pain. 123 (5) Monoxide Gas: NO and CO • Nitric Oxide (NO) – Exerts its effects by stimulation of cGMP. – Involved in memory and learning. – Smooth muscle relaxation. • Carbon monoxide (CO): – Stimulate production of cGMP within neurons. – Promotes odor adaptation in olfactory neurons. – May be involved in neuroendocrine regulation in hypothalamus. 124 Signal Transmission Between the Neurons Where there is a neurotransmission? Chemical Synapse, Non-synaptic chemical transmission, electrical synaps Excitatory and Inhibitory postsynaptic potentials. Synaptic Inhibition (presynaptic, postsynaptic, reciprocal, recurent) Spatial and temporal summation Divergent and convergent Synapse Classical Transmitters (small-molecule transmitters) Agonist and antogonist • Ionotropic channel Metabotropic channel • Acetylcholine Neurotransmission • Adrenergic Neurotransmission 125
