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Neurotransmission A nerve impulse initiated in a neuronal cell body, conducted through it’s axons up to the nerve ending and transmitted to other neuronal cells in succession and finally to the target cells. Target cell (Muscle cells) 1 Neurotransmission takes place by a) Electrical synapse b) Chemical synapse Electrical and chemical synapses differ fundamentally in their transmission mechanisms. A. At electrical synapses, gap junctions between pre- and postsynaptic membranes permit current to flow passively through intercellular channels. This current flow changes the postsynaptic membrane potential, initiating (or in some instances inhibiting) the generation of postsynaptic action potentials. B. At chemical synapses, there is no intercellular continuity, and thus no direct flow of current from pre- to postsynaptic cell. Synaptic current flows across the postsynaptic membrane only in response to the secretion of neurotransmitters which open or close postsynaptic ion channels after binding to receptor molecules. 2 3 Neurotransmission in through chemical synapse is mediated by Neurotransmitters Neurotransmitters are chemical signals released from pre synaptic nerve terminals into the synaptic cleft. The subsequent binding of neurotransmitters to specific receptors on postsynaptic neurons (or other classes of target cells) transiently changes the electrical properties of the target cells, leading to an enormous variety of postsynaptic effects. Criteria That Define a Neurotransmitter 1. The substance must be stored in the nerve endings. 2. The substance must be released in response to presynaptic depolarization, into the synaptic cleft and the release must be Ca2+-dependent. 3. Specific receptors for the substance must be present on the postsynaptic cell 4. Mechanism must be present in the synaptic region for the rapid removal of the substances. 4 Demonstrating the identity of a neurotransmitter at a synapse requires showing (1) its presence, (2) its release, and (3) the postsynaptic presence of specific receptors 5 Localization of neurotransmitter action. Neurotransmitters in general act either locally (A), by altering the electrical excitability of a small region of a single postsynaptic cell, or more diffusely (B), by altering the electrical excitability of a few postsynaptic cells. (C) Neurons can exert their actions over greater distances by having long axons that locally release neurotransmitters onto distant targets. 6 Mechanism of neurotransmitter release 7 A model for Ca2+-triggered vesicle fusion. SNARE proteins on the synaptic vesicle and plasma membranes form a complex that brings together the two membranes. Ca2+ then binds to synaptotagmin on the vesicle membrane, causing the cytoplasmic region of this protein to insert into the plasma membrane and 8 catalyze membrane fusion. Toxins That Affect Transmitter Release Tetanus toxin and botulinum toxin (types B, D, F, and G) specifically cleave the vesicle SNARE protein, synaptobrevin. Other botulinum toxins are proteases that cleave syntaxin (type C) and SNAP-25 (types A and E), SNARE proteins found on the presynaptic plasma membrane. Destruction of these presynaptic proteins is the basis for the actions of the toxins on neurotransmitter release. 9 Chain of events Action potential reaches the nerve ending Nerve ending membrane depolarizes Voltage gated Ca2+ channel opens and Ca2+ enters into the nerve endings Synaptic vesicles are fused with nerve ending membrane with the help of SNARE complex and this fusion is triggered by Ca2+ Neurotransmitters are released from the synaptic vesicle into the synaptic cleft Neurotransmitters binds with the specific receptors located in the post synaptic membrane 10 Neurons Often Release More Than One Transmitter Low-frequency stimulation preferentially raises the Ca2+ concentration close to the membrane, favoring the release of transmitter from small clear-core vesicles docked at presynaptic specializations. High-frequency stimulation leads to a more general increase in Ca2+, causing the release of peptide neuro transmitters from large densecore vesicles as well as smallmolecule neurotransmitters from small clear-core vesicles. 11 End of lecture 1 12 Major Categories of Neurotransmitters 13 A neurotransmitter can affect the activity of a postsynaptic cell via two different types of receptor proteins: ionotropic or ligand-gated ion channels, and metabotropic receptors. (A) Ligand-gated ion channels combine receptor and channel functions in a single protein complex. (B) Metabotropic receptors usually activate G-proteins, which modulate ion channels directly or indirectly through 14 intracellular effector enzymes and second messengers. Neurotransmitter can induce two types of response based on the property of the receptor 1) It may depolarize the post synaptic membrane giving rise to Excitatory post synaptic potential (EPSP) 2) It may hyperpolarize the post synaptic membrane giving rise to Inhibitory post synaptic potential (IPSP) The nature of the post synaptic potential (EPSP pr IPSP) depends upon the nature of the receptor not on the neurotransmitter itself. Thus the same neurotransmitter may have excitatory at one synapse and inhibitory at other. For ex Acetylcholine. It exerts IPSP at heart muscle but EPSP at neuro-muscular junction. It is known as Dale’s principle 15 Removal of the neurotransmitters in synaptic cleft 1) Enzymatic hydrolysis of neurotransmitters in the synaptic junctions. Ex: a) Acetylcholine is hydrolyzed by the Acetylcholine esterase b) Nucleotidase is involved in the degradation of ATP in synapse. 2) Reuptake of neurotransmitters from the synaptic cleft by the specific receptor located in the pre-synaptic membrane or in adjacent glial cells. Ex: Aminergic neurotransmitters such as epinephrine, nor epinephrine and serotonin are reuptaken shortly after their release into synaptic cleft. 3) Photolytic cleavage of the peptide neurotransmitters or neuropeptides. 16 Neurotransmitter Release and Removal Neurotransmitter Postsynaptic effect Rate-limiting step in synthesis Removal mechanism Type of vesicle ACh Excitatory Choline + acetyl CoA CAT AChEase Small, clear Glutamate Excitatory Glutamine Glutaminase Transporters Small, clear GABA Inhibitory Glutamate GAD Transporters Small, clear Glycine Inhibitory Serine Phosphoserine Transporters Small, clear Catecholamines (epinephrine, norepinephrine, dopamine) Excitatory Tyrosine Tyrosine hydroxylase Transporters, MAO, COMT Small densecore, or large irregular dense-core Serotonin (5-HT) Excitatory Tryptophan Tryptophan hydroxylase Transporters, MAO Large, dense-core Histamine Excitatory Histidine Histidine decarboxylase Transporters Large, dense-core ATP Excitatory ADP Mitochondrial oxidative phosphorylation; glycolysis Hydrolysis to AMP and adenosine Small, clear Neuropeptides Excitatory and inhibitory Amino acids (protein synthesis) Synthesis and transport Proteases Large, dense-core 17 Precursor(s) Neurotransmitter Synthesis The Biogenic Amines There are five established biogenic amine neurotransmitters: the three catecholamines—dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline)—and histamine and serotonin. 18 Histamine and Serotonin 19 Degradation Neural : Through the action of Mono amine oxidase (MAO) Extra neural: Through Catecholamine O methyl transferase Biogenic Amine Neurotransmitters and Psychiatric Disorders Reserpine: it blocks the vesicular monoamine transporter (VMAT) which normally transport free nor epinephrine , dopamine and serotonin from the cytoplasm into synaptic vesicle in the post synaptic nerve endings thus ultimately inhibits the release of these neurotransmitters into synaptic cleft. USE: to control high blood pressure. Side effects: Change of mood, Depression etc. MAO inhibitors: MAO inhibitors such as phenelzine block the breakdown of amines, serotonin uptake blockers such as fluoxetine (Prozac®) and trazodone—all influence various aspects of aminergic transmission. The extraordinarily popular antidepressant fluoxetine (Prozac®) selectively blocks the reuptake of serotonin without affecting the reuptake of catecholamines. 20 GABA The enzymes required for this degradation, GABA aminotransferase and succinic semialdehyde dehydrogenase, are both mitochondrial enzymes. Inhibition of GABA breakdown causes a rise in tissue GABA content and an increase in the activity of inhibitory neurons. Drugs that act as agonists or modulators on receptors, such as benzodiazepines and barbiturates, are effective sedatives and anesthetics. 21 Glycine Glycine can be synthesized by a number of metabolic pathways; in the brain, the major precursor is serine. High-affinity transporters terminate the actions of these transmitters and return GABA or glycine to the synaptic terminals for reuse. Mutations in the genes coding for some of these enzymes result in hyperglycinemia, a devastating neonatal disease characterized by lethargy, seizures, and mental retardation. 22 Glutamate Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and must be synthesized in neurons from local precursors. The most prevalent glutamate precursor in synaptic terminals is glutamine. Glutamine is released by glial cells and, once within presynaptic terminals, is metabolized to glutamate by the mitochondrial enzyme glutaminase. Glutamate synthesis and cycling between neurons and glia. The action of glutamate released into the synaptic cleft is terminated by uptake into neurons and surrounding glial cells via specific transporters. Within the nerve terminal, the glutamate released by glial cells and taken up by neurons is converted 23 back to glutamine. Acetylcholine Acetylcholine is the neurotransmitter at neuromuscular junctions, at synapses in the ganglia of the visceral motor system, and at a variety of sites within the central nervous system. Acetylcholine is synthesized in nerve terminals from acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline, in a reaction catalyzed by choline acetyltransferase (CAT). In contrast to most other small-molecule neurotransmitters, the postsynaptic action of ACh at many cholinergic synapses (the neuromuscular junction in particular) are not terminated by reuptake but by a powerful hydrolytic enzyme, AChE. 24 Acetylcholine esterase inhibitors Diisoproplyphosphofluorine Succinyl choline 25 Cholinergic receptor The AchR is a pentameric supermolecule structure formed by 2 α, 1 β, 1γ and 1 δ subunits. Each receptor subunit crosses the membrane four times. 2 molecules of acetylcholine bind with each of 2 α chain leading to the transient opening of Na+ channels of the postsynaptic membrane. The openings at either end of the channel are very large—approximately 3 nm in diameter; even the narrowest region of the pore is approximately 0.6 nm in diameter. By comparison, the diameter of Na+ or 26 K+ is less than 0.3 nm. Inhibitors of Cholinergic receptor Active compound in cuarare is d-tubocurarine: Interacts reersibly with cholinergic receptor at the neuromuscular junction. Other inhibitors are neurotoxins found in venoms of various poisonous snakesn. Ex: Alpha Bungarotoxin of Bungaris multicinctus and Cobra toxin from Cobra snake. Agonists: Nicotine, Muscarine 27 End of lecturer 2 28 GABA receptor GABA is the major inhibitory neurotransmitter in the mammalian CNS and, like glutamate and other transmitters, acts via both ligand gated ion channels (GABAA receptors) and G-protein coupled (GABAB) receptors. GABAA receptors are members of the ionotropic receptor superfamily which includes a-adrenergic and glycine receptors, while the GABAB receptor is a member of the receptor superfamily including the Glu receptors. 29 Dopaminergic receptor 2 types of Dopaminergic receptor have been identified a) D1 which is involved in the enhancement of the adenylate cyclase activity and is blocked selecting by phenothiazine tranquilizers such as trifluoperazine. b) D2 is associated with a reduction of adenylate cyclase acitivity and is blocked by butyrophenone neuroleptics such as haloperidol and spiperone. D2 subtype of dopaminergic receptor but not D1 are cleosely related to the antipsychotic action of the neuroleptic drug due to the related affinity of the drug for D2. 30 D1-like Dopamine receptor structure: 3 major segments. 1 extracellular chain, 3 Extracellular loops (E1-E3); 7 Transmembrane domains (1-7); 2 Intracellular loops (I2-I3) and 1 intracellular chain. Residues involved in dopamine binding are highlighted in transmembrane domains: Phe and Ser. Potential phosphorylation sites are represented on 3rd intracellular loop (I3) and on COOH terminus. Potential glycosylation sites are represented on NH2 terminal. D2-like receptors are characterized by a shorter COOH-terminal tail. 31 Adrenergic receptor 2 major types of adrenergic receptors are known in the nervous system: α and β. Each type exists in subtypes: α1 and α2; β1 and β2. α1 receptor is postsynaptic in the sympathetic system. α2 is mainly presynaptic in the extra neural region and regulates the release the nor-epinephrine while in central nervous system α2 is mainly postsynaptic. Both β1 and β2 receptors are postsynaptic in brain 32 Receptor type Agonist potency order α1: norepinephrine ≥ epinephrine >> isoproterenol α2: β1 β2 norepinephrine ≥ epinephrine >> isoproterenol isoprenaline > epinephrine = norepinephrine isoprenaline > epinephrine >> norepinephrine Selected action of agonist smooth muscle contraction Mechanism Phospholipase C (PLC) activated, IP3 and calcium up smooth muscle contraction and neurotransmitter inhibition Adenylate cyclase inactivated, cAMP down heart muscle contraction Adenylate cyclase activated, cAMP up smooth muscle relaxation Adenylate cyclase activated, cAMP up Agonists Antagonists Phenylephrine Methoxamine Alfuzosin Doxazosin Phenoxybenzami ne Dexmedetomidin e Clonidine Lofexidine •Noradrenaline •Isoprenaline •Dobutamine Salbutamol Albuterol •Bitolterol mesylate •Formoterol •Isoprenaline Yohimbine Idazoxan • Metoprolol •Atenolol •Practato •Butoxamine •Propranolol 33 Peptide Neurotransmitters 34 Peptide Neurotransmitter propeptide precursors are typically larger than their active peptide products and can give rise to more than one species of neuropeptide. Hence, the release of multiple neuroactive peptides from a single vesicle often elicits complex postsynaptic responses. The maturation of the prepropeptides involves cleaving the signal sequence and other proteolytic processing. Such processing can result in a number of different neuroactive peptides such as ACTH, γ-lipotropin, and β-endorphin (A), or multiple copies of the same peptide, such as metenkephalin (B). 35 Functions of neuropeptides Neurotensin has been implicated in the modulation of dopamine signaling As a neuropeptide, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. In humans, it has been suggested that CCK administration causes nausea and anxiety. CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. Substance P is one of the important complex mechanisms involved in pain perception.The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. Then somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial portal circulation. These blood vessels carry somatostatin to the anterior pituitary gland, where somatostatin inhibits the secretion of growth hormone from somatotrope cells. An enkephalin is a pentapeptide involved in regulating pain in the body. 36