Inhibitory NeurotransmittersMost common in CNS are gaba (-aminobutyric acid) and glycine
GlycineMade from serineUsed in spinal cord neurons at about 50% of inhibitory synapsesThe other 50% use gaba
StrychnineRat poison that blocks inhibitory neurotransmitter and cause excitation in CNSBlocks glycine receptor that leads to membrane depolarizations and over activity and death due to seizures
GabaMost frequently used inhibitory NT in brain & spinal cord. 1/3 of synapses use gabaPrecursors are glucose, pyruvate and glutamineGAD= glutamic acid decarboxylase converts glutamine to gabaRequires vitamin B6 derivative for GAD activity, so B6 deficiency can cause gaba deficiencyNoted when infant formula lacked B6=fatal seizures
Re-Uptake MechanismsSpecific Transport proteins on presynaptic membrane to reuptake intact NTRe-uptake into glial cellDiffusionDegradation by enzymes and re-uptake of metabolite
Gaba RemovalHigh affinity gaba transportersDegradative enzymes are mitochondrial
Multiple IsoformsEach subunit can be encoded by any one of several gene or mRNA products to make 3 subtypes of receptors A and C are ionchannels, B is a metabotropic receptorGABA receptor6 alpha subunit isoforms3 beta subunit isoforms2 gamma subunit isoforms
From webvisionmed.utahThe GABA a and c receptor are members of the ligand-gated channel superfamily. By analogy to the well studied nicotinic acytocholine receptors, GABAc receptors are thought to exhibit the structure shown schematically in Fig. 2. These receptors are pentomers, i.e. five subunits constitute the functional channel (Amin and Weiss, 1996). The receptors have a long extracellular domain containing ligand binding sites and several modulatory sites. In the middle of the receptor, GABA gates an ionic channel. Binding of GABA to the receptor induces a conformational change in receptor structure which leads to the opening of the channel.
Neurotransmitter Receptors100s NTs and 1000s or more NTRsReceptors w/o NTs
Multiple Receptors for 1 NTHow are they identified & classified How is this information used clinically?
Survey of NT Receptors
Figure 6-7:The neuropharmacology of cholinergic synaptic transmission
LigandFrom Latin means to bind (ligare)Any substance that binds a receptor or ion channelNeurotransmittersPlant & animal toxinsChemically synthesized compound
MAchRAtropine, derived from belladona flowerAntagonizes mAChRAch effect on pupil of the eye is to constrictForm of atropine is used in dilatory eye drops by opthamologists
Basic Structure of NT gated ion channel100 nm long-barely extends the width of pmSubunits arranged to form a barrel with interior pore through pmAll subunits have common domains named M1-M4 that are transmembraneM1-4 form hyophobic alpha helicesMost are composed of 4-5 subunits
Drugs that bind GABAa Receptors
BarbituatePhenobarbital = anestheticBenzodiazapines = tranquilizersvalium Binds GABAa subtype with gamma subunit
Effect of Drugs on GABA channels
In the absence of GABA, drugs have no effectIn the presence of GABA, drugs can Increase frequency of opening/benzodiazepinesIncrease duration of opening/barbituates
Pharmacology of VALIUMValium=benzodiazapines bind to gaba gated chloride channelCause the channel to stay open longer==less brain activity=calmer state of mindUsed as anti-convulsant drugs
Edvard Munch, the screamFear and Anxiety and Gaba A modulatorsAnxiolytic drugs-Librium valium
Thebrainmcgill.caSynapses-GabaAnxietyReceptorBy bindingBenzodiazepineBackThree typesMetabotropic vs ionotropicBack to anxiety NTNot the only RapheHormonal brain
NeuromodulationMetabotropic Ion ChannelsNeurotransmitters bind Receptors that are not ion channels
NeuromodulationNeurotransmitter binding and ion flux are provided by two or more individual molecules.Allows for many effects of NT on post-synaptic cellCan regulate several channels, metabolic enzymes and gene expressionStimulates or inhibits second messengers
Effect of Second Messenger
May directly bind ion channel and regulates its opening or closing
Can activate enzyme s.a. cyclic AMP dependent PKA that phosphorylates ion channel to open or close it
Effect of Symp & Parasym on Cardiac MuscleParasympathetic presynaptic nerve ending release Ach and slows heart rate Sympathetic presynaptic nerve ending release NE and increase heart rateBOTH WORK THROUGH NEUROMUDULATION USING G PROTEINS.
Parasympathetic Cardiac NeuromodulationAch binds muscarinic Ach Receptor that inhibits cardiac muscle excitationAch binds receptor and the G protein alpha subunit binds a potassium channelThe K channel opens, hyperpolarizes the cardiac membrane and leads to prolonged relaxation phase of cardiac activity=slows heart rate
Sympathetic Cardiac NeuromodulationAch binds B adrenergic Receptor that strengthen cardiac muscle contractilityNE binds B adrenergic receptor and the G protein alpha subunit activates Adenyl cyclase which produces cAMPcAMP activates PKA which phosphorylates voltage gated calcium channel, prolonging its opening time
NeuromodulationEffects mediated by second messengersDirect postsynaptic effects last several hundred milliseconds to hoursSecondary effects lasts daysPostsynaptic electrical responses are weak and slow
Second MessengerscAMPcGMPGTPCalciumDAG and IP3Arachidonic acidMay act directly or indirectly on ion channel
How do G-proteins WorkCan inhibit or activate downstream molecules to increase or decrease levels of second messengers
Denoted Gs or Gi
G-proteins Link Channel Activity with NT GTP-binding protein cycles between off state (GDP bound) and on state (GTP- bound)NT receptors catalyzes replacement of GDP with GTP.Activated G-protein activates adenylyl cyclase that produces cAMP
Short Cut PathwayNT binds receptor that is not an ion channel but is linked to trimeric G proteinG protein becomes activated by conformational change transduced from NTR that allows G to bind GTPDissociates into a and bg subunit componentsGb subunit binds directly to ion channel & gates it.
Long-Term EffectsIon channel can be regulated by G-protein directly and by second messengers and enzymes s.a. PKA.So the effect of neurotransmitter binding can have prolonged effects on ion channel activity.An activated NT receptor can bind to many G proteins so signal is amplified700 types of G proteins
G Protein Linked to Adenylyl CyclaseCauses formation of cAMP and activation of PKAPKA phosphorylates serine and threonine residues on target proteins
Regulation of G protein Some NT bind to both Gi and Gs linked receptors
NeuromodulationAllows for amplification of NT signalAllows for long term changes in post synaptic membrane
G Proteins linked to PhospholipasePhospholipase cleaves PIP2 in the membraneGenerates to metabolic products each are second messengersIP3 and DAGIP3 causes calcium release from intracellular storesDAG activate PKC
Nitric Oxide (NO)Made from arginine by NO synthaseChemical exist gas formReleased from post-synaptic terminal without vesicles and acts on presynaptic terminal = retrograde communication aka retrograde messengerLifetime is 5-10 min
NO relaxes Blood VesselsNO production is induced by ACh released from parasympathetic nerve endings onto endothelial cells in blood vessels mAchR activation leads to activation of NO synthase & production of NONO diffuses into underlying smooth muscle cells
NO EffectBinds iron co-factor in the active site of guanylyl cyclaseEnzyme that forms cGMP for GTPLeads to increase cGMP cGMP leads to smooth muscle relaxationIncreasing diameter of blood vessel and enhances blood flow
Viagra inhibits PDE5
Phosphodiesterase degrades cGMP into GMP Viagra inhibits PDE5 isoform expressed primarily in penisEnd result is prolonged increased levels of cGMP in smooth muscle allows increased blood flow into the cavernous tissue of the penis thereby generating an erection
Viagra started life as a medicine intended to treat angina pectoris.Alfred Nobel - an explosives manufacturer - suffered from angina. In 1890 he was prescribed nitroglycerine (called trinitrin) to relieve the pain of angina attacks. It is still used today.Over 100 years later, the work of Robert Furchgott, Louis Ignarro and Ferid Murad showed that nitric oxide (NO) was an important signalling molecule in the cardiovascular system. It is released from nerve endings and cells lining the walls of blood vessels. The effect is to make the blood vessel relax, or dilate. It is also involved in the prevention of blood clots. In 1998, they received the Nobel Prize for Physiology. The Nobel prizes were set up by the same Alfred Nobel who had been treated with nitroglycerine
Viagra was a failed anti-angina medicine
9 types of PDEPDE5 is expressed in erectile tissue of penis and in the retina
Giles Brindley and Drug Therapy for ED Modern drug therapy for ED was advanced enormously in 1983 when British physiologist Giles Brindley, Ph.D. dropped his trousers and demonstrated to a shocked AUA audience his phentolamine-induced erection. The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered, established the fundamentals for the later development of specific, safe, orally-effective drug the
