4Neurotransmitter A chemical substance that is Synthesized in a neuron. Stored in presynaptic nerve terminal.Released into synaptic cleft.Act upon the postsynaptic neuron, muscle or organ.Synthesisof neurotransmitterAxon of a neuronStored neurotransmitterPresynaptic membraneAxon terminalPostsynaptic membraneSynaptic cleftPostsynaptic membrane receptorsEffect specific to target tissue
5Classification of Neurotransmitters Type of SubstanceExamplesEsterAcetylcholineAmino acidsGlycineGamma amino butyric acid (GABA)GlutamateAspartateAminesCatecholaminesEpinephrine (Adrenaline)Norepinephrine (Noradrenaline)DopamineIndolaminesSerotoninHistamineTaurinePeptidesEndorphins, enkephalins, substance P, cholecystokininOthersATP, NO, CO
6Functional Classification ExamplesExcitatory(leads to depolarization )GlutamateAspartateSerotoninHistamineATP, COInhibitory(leads to hyperpolarization )GlycineGamma amino butyric acid (GABA)TaurineExcitatory & Inhibitory(leads to depolarization and hyperpolarization depending on type of receptor )AcetylcholineEpinephrine (Adrenaline)DopamineNorepinephrine (Noradrenaline)NOEndorphins, enkephalins, substance P, cholecystokinin
7Acetylcholine esterase Synthesized from acetyl CoA and choline.Stored in presynaptic terminalReleased into synaptic cleftAct upon the postsynaptic receptorsReceptors are two typesMuscarinic, NicotinicAcetylcholine esterase hydrolyzes acetylcholine.Acetyl CoA+CholineAcetylcholine esteraseMuscarinic2.NicotinicEffect specific to target tissue
8Types of Cholinergic Receptors MuscarinicNicotinicAcetylcholine
9Types of Cholinergic Receptors Receptor TypeNatural StimulatorsLocation of receptorsMechanism of actionMuscarinic1.Ach2.MuscarineCNS (M1-M5)Secretory glands e.g., Salivary, stomach & Sweat glands (M1)Cardiac tissue (M2)Smooth muscles (M3)Parasympathetic systemM1, M3 & M5 activation of phospholipase C IP3 & DAG generation increased calciumM2 & M4 inhibition of adenylate cyclase decreased cAMPNicotinic2.NicotineCNSNeuromuscular junctionAutonomic gangliaAdrenal medullaActivation of nicotinic receptors opening of Na+ and K+ channels depolarization
10Distribution of Cholinergic Receptors CNSPeripheral Nervous SystemAChNicAChMuscarinicParasympatheticAChNictinic:Adrenal medullaSympatheticAChNicNEAdrenergic:Heart and blood vesselsAChNicAChMuscarinic:Sweat glandsAChNicotinic:Skeletal musclesSomatic
12kulsoomCatecholaminesEpinephrineCatecholamines are derivatives of tyrosine & contain a catechol (dihydroxybenzene) ring.The difference between epinephrine and norepinephrine: one additional methyl group in structure of epinephrine.The difference between norepinephrine and dopamine: one additional hydroxyl group in the structure of norepinephrine.(Adrenaline)Norepinephrine(Noradrenaline)2DopamineH2
16Adrenergic receptors are seven-pass transmembrane proteins. kulsoomAdrenergic ReceptorAlphaBetakulsoomAlpha 1Alpha 2Beta 1Beta 2Beta 3Adrenergic receptors are seven-pass transmembrane proteins.
17Mechanism of ActionThese are called G protein-coupled receptors (GPCRs).The three subunits are: Gα, Gβ, GγGα carries the binding site for the nucleotide and is different in different types of G proteins Gs, Gi and Gq.GαββGiαGsαGqαG proteins are so-called because they bind the guanine nucleotides, GDP and GTP.They are heterotrimers (i.e., made of three different subunits) associated with the inner surface of the plasma membrane andtransmembrane receptors of hormones.These are called G protein-coupled receptors (GPCRs).The three subunits are:Gα,.GβGγGα carries the binding site for the nucleotide and is different in different types of G proteins Gs, Gi and Gq.Gβ and Gγ are same in all types of G proteins.Gβ and Gγ are same in all types of G proteins.
19= Adrenaline & Noradrenaline kulsoom= Adrenaline & Noradrenaline1Gq2GiGsPhospholipace CAdenylate cyclaseAdenylate cyclasePIP2DAGIP3Ca2+Ca2+DecreasedcAMPIncreasedcAMPIncreasedDecreasedInhibition of neurotransmitter release from neuronSmooth muscle ContractionSmooth muscle ContractionGlycogen breakdownSmooth muscle relaxesCardiac muscle contractsEffector cell= inhibits= leading to
20Effect of Autonomic NS on Heart Parasympathetic Nerves (Vagus)Sympathetic Nerves& NorepinephrineAChNE21M2↑ heart rate↑ conduction velocity↑contractility↑ rate of myocyte relaxation_+CardiomyocyteKulsoom animated from
21Distribution of Adrenergic Receptor kulsoomDistribution of Adrenergic ReceptorE = EpinephrineAt low epinephrine concentrations, the beta-2 adrenergic receptors will be occupied because these receptors have a higher affinity for epinephrine.At high epinephrine concentrations, the alpha-1 adrenergic receptors will be occupied too. Because there are more alpha-1 receptors the predominant effect at high epinephrine concentration is vascular smooth muscle contraction.
22Dopamine Precursor Phenylalanine Site of synthesis CNS, heart, pulmonary artery, kidney.ReceptorD1-D5 (G-protein coupled)EffectExcitatory (D1), Inhibitory (D2). Involved in movement, cognition, pleasure, and motivationDiseaseDecreased levels leads to Parkinson’s Disease and high levels are observed in schizophrenia.
23Glycine Precursor Serine Site of synthesis CNS Receptor Glycine-A & B, NMDAEffectExcitatory: motor functionNMDA=N-methyl-D-aspartate
24Aspartic Acid L-Aspartate Precursor Oxaloacetate Site of synthesis CNS ReceptorNMDA receptorsEffectExcitatory: Learning and memory.NMDA=N-methyl-D-aspartate
25Glutamate Precursor -ketoglutarate Site of synthesis CNS Receptor AMPA, NMDA, kainate, metabotropicEffectExcitatory: include cognition, memory and learning.AMPA = amino-methyl propanoic acid
26-aminobutyric acid (GABA) CO2Synthesis:Glutamate decarboxylase-aminobutyric acid (GABA)GlutamateGABAPrecursorGlutamateSite of synthesisCNSReceptorGABA-A & BEffectInhibitory: include cognition, memory and learning.
27(5-hydroxytryptamine) SerotoninSynthesis:Hydroxylation & decarboxylationSerotonin(5-hydroxytryptamine)TryptophanSerotoninPrecursorTryptophanSite of synthesisIntestinal mucosal cells, CNSReceptor5HTA-FEffectExcitatory: include pain perception, regulation of sleep, appetite, temperature, blood pressure, cognitive functions & mood.DiseaseDecreased levels leads to some types of depression.
28Histamine Precursor Histidine Site of synthesis CNS, basophils, mast cellReceptorH1-H4EffectExcitatory:, sleep regulation, smooth muscle constriction, (acid secretion by stomach & immune system).DiseaseLow levels in CSF in Schizophrenia.
29Neuropeptides Neuropeptides There are around 200 neuropeptides identified.NeuropeptidesPrecursorAmino acids form large peptide which are cleaved to form short peptides.Examples-Endorphins, Met- enkephalins, Somatostatin, Substance P, CCK etc.Site of synthesisCNS, ANS, GIT (mainly)ReceptorG- protein coupled seven helical transmembrane proteinsEffectExcitatory & inhibitory: hunger, thirst, pleasure, pain, learning & memory.
30Miscellaneous Neurotransmitters ATP:Is found in both the CNS and PNSProduces excitatory or inhibitory responses depending on receptor type.Induces Ca2+ wave propagation in astrocytesProvokes pain sensationNitric oxide (NO) :Activates the intracellular receptor guanylyl cyclaseinvolved in learning and memory.Carbon monoxide (CO):a main regulator of cGMP in the brain