Table of Neurotransmitters Synaptic Transmission Neuromuscular Transmission Neurotransmitter Receptors Acetylcholine Cholinergic Agonists and Antagonists Catecholamines Serotonin

GABA
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Table of Neurotransmitters
Transmitter Molecule Acetylcholine Derived rom Site of Synthesis Choline CNS! parasympathetic nerves Serotonin CNS! chromaffin cells of the gut! enteric Tryptophan "#$ydro%ytryptamine &"#$T' cells GABA Glutamate Aspartate Glycine $istamine (pinephrine synthesis path)ay Norpinephrine synthesis path)ay Dopamine synthesis path)ay Adenosine AT* Nitric o%ide! N+ Arginine $istidine Tyrosine Tyrosine Tyrosine AT* Glutamate CNS CNS CNS spinal cord hypothalamus adrenal medulla! some CNS cells CNS! sympathetic nerves CNS CNS! peripheral nerves sympathetic! sensory and enteric nerves CNS! gastrointestinal tract

Many other neurotransmitters are derived from precursor proteins! the so#called peptide neurotransmitters, As many as "- different peptides have been sho)n to e%ert their

effects on neural cell function, Several of these peptide transmitters are derived from the larger protein pre#opiomelanocortin &*+MC', Neuropeptides are responsible for mediating sensory and emotional responses including hunger! thirst! se% drive! pleasure and pain, The imbalance of ones neuropeptides can be a cause of chemical dependency, Addiction rehabilitation centers are available for help and for more information! chec. out our rehab guide or N/DA, bac. to the top

Synaptic Transmission
Synaptic transmission refers to the propagation of nerve impulses from one nerve cell to another, This occurs at a speciali0ed cellular structure .no)n as the synapse! a 1unction at )hich the a%on of the presynaptic neuron terminates at some location upon the postsynaptic neuron, The end of a presynaptic a%on! )here it is 1u%taposed to the postsynaptic neuron! is enlarged and forms a structure .no)n as the terminal button, An a%on can ma.e contact any)here along the second neuron2 on the dendrites &an a%odendritic synapse'! the cell body &an a%osomatic synapse' or the a%ons &an a%o#a%onal synapse', Nerve impulses are transmitted at synapses by the release of chemicals called neurotransmitters, As a nerve impulse! or action potential! reaches the end of a presynaptic a%on! molecules of neurotransmitter are released into the synaptic space, The neurotransmitters are a diverse group of chemical compounds ranging from simple amines such as dopamine and amino acids such as 3#aminobutyrate &GABA'! to polypeptides such as the en.ephalins, The mechanisms by )hich they elicit responses in both presynaptic and postsynaptic neurons are as diverse as the mechanisms employed by gro)th factor and cyto.ine receptors, bac. to the top

Neuromuscular Transmission
A different type of nerve transmission occurs )hen an a%on terminates on a s.eletal muscle fiber! at a speciali0ed structure called the neuromuscular junction, An action potential occurring at this site is .no)n as neuromuscular transmission, At a neuromuscular 1unction! the a%on subdivides into numerous terminal buttons that reside )ithin depressions formed in the motor end#plate, The particular transmitter in use at the neuromuscular 1unction is acetylcholine, bac. to the top

Neurotransmitter Receptors

+nce the molecules of neurotransmitter are released from a cell as the result of the firing of an action potential! they bind to specific receptors on the surface of the postsynaptic cell, /n all cases in )hich these receptors have been cloned and characteri0ed in detail! it has been sho)n that there are numerous subtypes of receptor for any given neurotransmitter, As )ell as being present on the surfaces of postsynaptic neurons! neurotransmitter receptors are found on presynaptic neurons, /n general! presynaptic neuron receptors act to inhibit further release of neurotransmitter, The vast ma1ority of neurotransmitter receptors belong to a class of proteins .no)n as the serpentine receptors, This class e%hibits a characteristic transmembrane structure2 that is! it spans the cell membrane! not once but seven times, The lin. bet)een neurotransmitters and intracellular signaling is carried out by association either )ith G# proteins &small GT*#binding and hydroly0ing proteins' or )ith protein .inases! or by the receptor itself in the form of a ligand#gated ion channel &for e%ample! the acetylcholine receptor', +ne additional characteristic of neurotransmitter receptors is that they are sub1ect to ligand#induced desensiti0ation2 That is! they can become unresponsive upon prolonged e%posure to their neurotransmitter, bac. to the top

Acetylcholine
Acetylcholine &ACh' is a simple molecule synthesi0ed from choline and acetyl#CoA through the action of choline acetyltransferase, Neurons that synthesi0e and release ACh are termed cholinergic neurons, 4hen an action potential reaches the terminal button of a presynaptic neuron a voltage#gated calcium channel is opened, The influ% of calcium ions! Ca56! stimulates the e%ocytosis of presynaptic vesicles containing ACh! )hich is thereby released into the synaptic cleft, +nce released! ACh must be removed rapidly in order to allo) repolari0ation to ta.e place7 this step! hydrolysis! is carried out by the en0yme! acetylcholinesterase, The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid,

Synthesis of Acetylcholine
ACh receptors are ligand#gated cation channels composed of four different polypeptide subunits arranged in the form 8&95'&:'&3'&;'<, T)o main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool al.aloid! muscarine! and to nicotine! respectively2 the muscarinic receptors and the nicotinic receptors,

Both receptor classes are abundant in the human brain, Nicotinic receptors are further divided into those found at neuromuscular 1unctions and those found at neuronal synapses, The activation of ACh receptors by the binding of ACh leads to an influ% of Na6 into the cell and an efflu% of =6! resulting in a depolari0ation of the postsynaptic neuron and the initiation of a ne) action potential, bac. to the top

Cholinergic Agonists and Antagonists

Numerous compounds have been identified that act as either agonists or antagonists of cholinergic neurons, The principal action of cholinergic agonists is the e%citation or inhibition of autonomic effector cells that are innervated by postganglionic parasympathetic neurons and as such are referred to as parasympathomimetic agents, The cholinergic agonists include choline esters &such as ACh itself' as )ell as protein# or al.aloid#based compounds, Several naturally occurring compounds have been sho)n to affect cholinergic neurons! either positively or negatively, The responses of cholinergic neurons can also be enhanced by administration of cholinesterase &Ch(' inhibitors, Ch( inhibitors have been used as components of nerve gases but also have significant medical application in the treatment of disorders such as glaucoma and myasthenia gravis as )ell as in terminating the effects of neuromuscular bloc.ing agents such as atropine, bac. to the top

Natural Cholinergic Agonist and Antagonists

Source of Compound Agonists Nicotine Muscarine 9#>atroto%in Antagonists al.aloid prevalent in the tobacco plant activates nicotinic class of ACh receptors! loc.s the channel open Mode of Action

al.aloid produced by Amanita activates muscarinic class of muscaria mushrooms ACh receptors induces massive ACh release! protein produced by the blac. possibly by acting as a Ca56 )ido) spider ionophore

al.aloid produced by the atropine &and related deadly nightshade! Atropa compound Scopolamine' belladonna Botulinus to%in 9#Bungaroto%in d#Tubocurarine bac. to the top eight proteins produced by Clostridium botulinum

bloc.s ACh actions only at muscarinic receptors inhibits the release of ACh

protein produced by Bungarus prevents ACh receptor channel genus of sna.es opening active ingredient of curare prevents ACh receptor channel opening at motor end#plate

Catecholamines
The principal catecholamines are norepinephrine! epinephrine and dopamine, These compounds are formed from phenylalanine and tyrosine, Tyrosine is produced in the liver from phenylalanine through the action of phenylalanine hydro%ylase, The tyrosine is then transported to catecholamine#secreting neurons )here a series of reactions convert it to dopamine! to norepinephrine and finally to epinephrine &see also Speciali0ed *roducts of Amino Acids',

Synthesis of the catecholamines from tyrosine

Catecholamines e%hibit peripheral nervous system e%citatory and inhibitory effects as )ell as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity, The e%citatory effects are e%erted upon smooth muscle cells of the vessels that supply blood to the s.in and mucous membranes, Cardiac function is also sub1ect to e%citatory effects! )hich lead to an increase in heart rate and in the force of contraction, /nhibitory effects! by contrast! are e%erted upon smooth muscle cells in the )all of the gut! the bronchial tree of the lungs! and the vessels that supply blood to s.eletal muscle, /n addition to their effects as neurotransmitters! norepinephrine and epinephrine can influence the rate of metabolism, This influence )or.s both by modulating endocrine function such as insulin secretion and by increasing the rate of glycogenolysis and fatty acid mobili0ation,

The catecholamines bind to t)o different classes of receptors termed the 9# and :# adrenergic receptors, The catecholamines therefore are also .no)n as adrenergic neurotransmitters7 neurons that secrete them are adrenergic neurons, Norepinephrine# secreting neurons are noradrenergic, Some of the norepinephrine released from presynaptic noradrenergic neurons is recycled in the presynaptic neuron by a reupta.e mechanism, The actions of norepinephrine and epinephrine are e%erted via receptor#mediated signal transduction events, There are three distinct types of adrenergic receptors2 9?! 95! :, 4ithin each class of adrenergic receptor there are several sub#classes, The 9? class contains the 9?A! 9?B! and 9?D receptors, The 9? receptor class are coupled to G@#type G# proteins that activate *>C3 resulting in increases in /*A and DAG release from membrane */*5, The 95 class contains the 95A! 95B! and 95C receptors, The 95 class of adrenergic receptors are coupled to Gi#type G#proteins that inhibit the activation of adenylate cyclase and therefore! activation results in reductions in cAM* levels, The : class of receptors is composed of three subtypes2 :?! :5! and :A each of )hich couple to Gs#type G#proteins resulting in activation of adenylate cyclase and increases in cAM* )ith concomitant activation of *=A, Dopamine binds to dopamineric receptors identified as D#type receptors and there are four subclasses identified as D?! D5! DB! and D", Activation of the dopaminergic receptors results in activation of adenylate cyclase &D? and D"' or inhibition of adenylate cyclase &D5 and DB',

Catecholamine Catabolism
(pinephrine and norepinephrine are cataboli0ed to inactive compounds through the se@uential actions of catecholamine#O#methyltransferase &C+MT' and monoamine o%idase &MA+', Compounds that inhibit the action of MA+ have been sho)n to have beneficial effects in the treatment of clinical depression! even )hen tricyclic antidepressants are ineffective, The utility of MA+ inhibitors )as discovered serendipitously )hen patients treated for tuberculosis )ith isonia0id sho)ed signs of an improvement in mood7 isonia0id )as subse@uently found to )or. by inhibiting MA+,

Metabolism of the catecholamine neurotransmitters, +nly clinically important en0ymes are included in this diagram, The catabolic byproducts of the catecholamines! )hose levels in the cerebrospinal fluid are indicative of defects in catabolism! are in blue

underlined te%t, Abbreviations2 T$ C tyrosine hydro%ylase! D$*R C dihydropteridine reductase! $5B C dihydrobiopterin! $BB C tetrahydrobiopterin! MA+ C monoamine o%idase! C+MT C catecholamine#O#methyltransferase! M$*G C A#metho%y#B# hydro%yphenylglycol! D+*AC C dihydro%yphenylacetic acid, bac. to the top

Serotonin
Serotonin &"#hydro%ytryptamine! "$T' is formed by the hydro%ylation and decarbo%ylation of tryptophan &see also Speciali0ed *roducts of Amino Acids',

*ath)ay for serotonin synthesis from tryptophan, Abbreviations2 T$* C tryptophan hydro%ylase! D$*R C dihydropteridine reductase! $5B C dihydrobiopterin! $BB C tetrahyrobiopterin! "#$T C "#hydro%ytryptophan! AADC C aromatic >#amino acid decarbo%ylase, The greatest concentration of "$T &D-E' is found in the enterochromaffin cells of the gastrointestinal tract, Most of the remainder of the bodyFs "$T is found in platelets and the CNS, The effects of "$T are felt most prominently in the cardiovascular system! )ith additional effects in the respiratory system and the intestines, Gasoconstriction is a classic response to the administration of "$T, Neurons that secrete "$T are termed serotonergic, ollo)ing the release of "$T! a portion is ta.en bac. up by the presynaptic serotonergic neuron in a manner similar to that of the reupta.e of norepinephrine, The function of serotonin is e%erted upon its interaction )ith specific receptors, Several serotonin receptors have been cloned and are identified as "$T?! "$T5! "$TA! "$TB! "$T"! "$TH! and "$TI, 4ithin the "$T? group there are subtypes "$T?A! "$T?B! "$T?D! "$T?(! and "$T? , There are three "$T5 subtypes! "$T5A! "$T5B! and "$T5C as )ell as t)o "$T" subtypes! "$T"a and "$T"B, Most of these receptors are coupled to G#proteins

that affect the activities of either adenylate cyclase or phospholipase C3, The "$TA class of receptors are ion channels, Some serotonin receptors are presynaptic and others postsynaptic, The "$T5A receptors mediate platelet aggregation and smooth muscle contraction, The "$T5C receptors are suspected in control of food inta.e as mice lac.ing this gene become obese from increased food inta.e and are also sub1ect to fatal sei0ures, The "$TA receptors are present in the gastrointestinal tract and are related to vomiting, Also present in the gastrointestinal tract are "$TB receptors )here they function in secretion and peristalsis, The "$TH and "$TI receptors are distributed throughout the limbic system of the brain and the "$TH receptors have high affinity for antidepressant drugs, bac. to the top

GABA
Several amino acids have distinct e%citatory or inhibitory effects upon the nervous system, The amino acid derivative! 3#aminobutyrate! also called B#aminobutyrate! &GABA' is a )ell#.no)n inhibitor of presynaptic transmission in the CNS! and also in the retina, Neurons that secrete GABA are termed GABAergic, The formation of GABA occurs by the decarbo%ylation of glutamate cataly0ed by glutamate decarbo%ylase &GAD', GAD is present in many nerve endings of the brain as )ell as in the :#cells of the pancreas, The activity of GAD re@uires pyrido%al phosphate &*>*' as a cofactor, *>* is generated from the BH vitamins &pyrido%ine! pyrido%al! and pyrido%amine' through the action of pyrido%al .inase, *yrido%al .inase itself re@uires 0inc for activation, A deficiency in 0inc or defects in pyrido%al .inase can lead to sei0ure disorders! particularly in sei0ure#prone preeclamptic patients &hypertensive condition in late pregnancy',

GABA synthesis
GABA e%erts its effects by binding to t)o distinct receptors! GABA#A and GABA#B, The GABA#A receptors form a ClJ channel, The binding of GABA to GABA#A receptors increases the Cl# conductance of presynaptic neurons, The an%iolytic drugs of the ben0odia0epine family e%ert their soothing effects by potentiating the responses of GABA#A receptors to GABA binding, The GABA#B receptors are coupled to an intracellular G#protein and act by increasing conductance of an associated =6 channel,

bac. to the top Return to The Medical Biochemistry *age Michael 4, =ing! *h,D K /L School of Medicine K mi.ing at iupui,edu K M ?DDHJ5-?? ast modified! March "#$ %&""