R E B 4 Med Students com 2003

R. E. B, 4 Med. Students. com, 2003 Neurotransmitters n Properties of neurotransmitters: 1) synthesized in the presynaptic neuron 2) Localized to vesicles in the presynaptic neuron 3) Released from the presynaptic neuron under physiological conditions 4) Rabidly removed from the synaptic cleft by uptake or degradation 5) Presence of receptor on the post-synaptic neuron. 6) Binding to the receptor elicits a biological response 1

2

Neurotransmitters found in the nervous system EXCITATORY Acetylcholine Aspartate Dopamine Histamine Norepinephrine Epinephrine Glutamate Serotonin INHIBITORY GABA Glycine 3

Acetylcholine synthesis: n In the cholinergic neurons acetylcholine is synthesized from choline. This reaction is activated by cholineacetyltransferase As soon as acetylcholine is synthesized, it is stored within synaptic vesicles. 4

Release of acetylcholine from presynaptic neurons: n n n n 1)When the nerve impulse (Action potential) moves down the presynaptic axon to the terminal bulb the change in the membrane action potential causes the opening of voltage gated calcium channels open allowing Ca+2 ions to pass from the synaptic cleft into the axon bulb. 2) Within the bulb the increase in Ca+2 concentration causes the synaptic vesicles that contain acetylcholine to fuse with the axonal membrane and open spilling their contents into the synaptic cleft. 5

Binding of acetylcholine to the postsynaptic receptors: n The postsynaptic membrane of the receptor dendrite has specific cholinergic receptors toward which the neurotransmitter diffuses. Binding of acetylcholine trigger the opening of ion channels in the postsynaptic membrane initiating action potential that can pass in the next axon. n. Acetylcholine receptors: n Acetylcholine receptors are ion channels receptors made of many subunits arranged in the form [(α 2)(β)(γ)(δ)]. • When Acetylcholine is not bounded to the receptors, the bulky hydrophobic leu side close the central channels preventing the diffusion of any ions. • Binding of two acetylcholine molecules to the receptors will rotate the subunits in which the smaller polar residues will line the ion channel causing the influx of Na+ into the cell and efflux of K+ resulting in a depolarization of the postsynaptic neuron and the initiation of new action potential. 6

Removal of Acetylcholine from the synaptic cleft: n n In order to ready the synapse for another impulses: 1) The neurotransmitters, which are released from the synaptic vesicles, are hydrolyzed by enzyme present in the synaptic cleft “Acetylcholinestrase” giving choline, which poorly binds to acetylcholine receptors. Acetylcholinestrase Acetylcholine + H 2 O n Choline + H+ acetate 2) The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis, must be filled with acetylecholine. 7

Structure of Ach. E n Acetylcholinesterase (Ach. E) is an enzyme, which hydrolyses the neurotransmitter acetylcholine. The active site of ACh. E is made up of two subsites, both of which are critical to the breakdown of ACh. The anionic site serves to bind a molecule of ACh to the enzyme. Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite. Here, the ester bond of ACh is broken, releasing acetate and choline. Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane. 8

Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine). n n 1) First Step: Hydroxylation: In this step: the reaction involves the conversion of tyrosine, oxygen and tetrahydrobiopterin to dopa & dihydrobiopterin. This reaction is catalyzed by the enzyme tyrosine hydroxylase. It is irreversible reaction. 2) Second step: Decarboxylation: In this step: the dopa decaboxylase will catalyze the decaoxylation of dopa to produce dopamine. The deficiency of this enzyme can cause Parkinson’s disease. It is irreversible reaction. The cofactor in this reaction is the PLP (pyridoxal phosphate). In the nerve cells that secrete dopamine as neurotransmitter the pathway ends at this step. 9

Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine). 3) Third step: Hydroxylation: This reaction is catalyzed by the enzyme dopamine β- hydroxylase. The reactants include dopamine, O 2 and ascorbate (vitamin C). The products are norepinephrine, water and dehydroascorbate. It is an irreversible reaction). The end product in noradrenergic cells is norepinephrine and the pathway ends her. 4) Forth step: Methylation: This reaction is catalyzed by phenylethanolamine Nmethyltransferase. Norepinephrine and S-adenosylmethionin (ado -Met) form epinephrine and S-adenosyl homocysteine (ado-Hcy). 10

11

Serotonin synthesis: • Serotonin is synthesized from the amino acid Tryptophan. • The synthesis of serotonin involve two reactions: 1) 1) Hydroxylation: Tryptophan 5 - Hydroxytryptophan • The enzyme catalyzes this reaction is Tryptophan Hydroxylase. • The Co- factor is Tetrahydrobiopterin, which converted in this reaction to Dihydrobiopterin. 2) 2) Decarboxylation: 5 - hydroxytryptophan Serotonin The enzyme is hydroxytryptophan decarboxylase. • Serotonin is synthesized in CNS, & Chromaffin cells. 12

13

Break down of serotonin: n Serotonin is degraded in two recations 1) Oxidation: 5 -hydroxytryptoamine + O 2 + H 2 O 2) Dehydrogenation 5 - Hydroxyinodole-3 -acetaldehyde Monoamine oxidase 5 - Hydroxyinodole-3 -acetaldehyde Aldehyde dehydrogenase 5 -hydroxindole-3 -acetate (Anion of 5 -hydroxyindoleacetic acid) 14

Other Neurotransmitters: Neurotransmitter Derived from Enzyme Histamine Histidine decarboxylase GABA (γ-Amino butyrate) Glutamate decarboxylase Nitric Oxide Arginine Nitric Oxide Synthase 15

Summary: Neurotransmitter Molecule Derived From Site of Synthesis Acetylcholine CNS, parasympathetic nerves Serotonin 5 -Hydroxytryptamine (5 -HT) Tryptophan CNS, chromaffin cells of the gut, enteric cells GABA Glutamate CNS Histamine Histidine hypothalamus Epinephrine synthesis pathway Tyrosine adrenal medulla, some CNS cells Norpinephrine synthesis pathway Tyrosine CNS, sympathetic nerves Dopamine synthesis pathway Tyrosine CNS Nitric oxide, NO Arginine CNS, gastrointestinal tract