Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 481Bi 1 Lecture 9 Thursday, April 13, 2006Synapses: Biophysical MachinesReminder: Henry Lester’s “office” hoursMon, Thurs 1-1:30 PM, outside the Red Door2Video on synaptic transmission3Narrated byLeonard Nemoy4Cerebral cortexAxonsDendrites SynapsesSynaptic vesicles (volleyballs), mitochondria (watermelons)1. Movements do not occur in 1 ms; vesicles are already “docked”.2. Neurotransmitter diffuses across the synaptic cleft in a few s3. There is little space between neurons4. “Slight” errors cause mental illness? Unproven!(But single-codon mutations do cause some neuroscience diseases)5Nestler Figure 2-2(rotated)Parts of two neuronssynaptic cleftdirection of information flowdendritesExcitatoryterminalcell body nucleus axonpresynaptic terminalpostsynaptic dendriteInhibitoryterminalpresynaptic terminalneuronPresynaptic neuronPostsynaptic Greek, “tree”Greek, “axis”from Lecture 46presynaptic neuron postsynaptic neuronThe synapse is a point of information processing An adult human brain contains ~ 1011 neurons, and each of these might receive 103 synapses apiece, for a total of 1014 synapses. Most of these synapses form during the first 2 yr of life. Thus 1014synapses/108 s = 106 synapses/s form in a fetus and infant!Nestler Box 2-3 Figure AGreek, “connection, junction”from Lecture 47cytosolreceptorcytosolsynaptic cleftreceptorreceptorChemistry is a language of the nervous system, for instance at synapsespresynaptic terminalpostsynaptic dendritedirection of information flowfrom Lecture 4transmitter moleculesin synaptic vesicles89Electron microscope image (“micrograph”) of a portion of a synapsesynaptic vesiclespresynaptic terminalpostsynaptic dendriteIt takes 3 different pump / transporter proteins to position the transmitter within the vesicles10 Na+-coupled cell membrane neurotransmitter transporters:Antidepressants (“SSRIs” = serotonin-selectivereuptake inhibitors):Prozac, Zoloft, Paxil, Celexa, LuvoxDrugs of abuse: MDMAAttention-deficit disorder medications:Ritalin, Dexedrine, Adderall,Strattera (?)Drugs of abuse: cocaine amphetamineNa+-coupledcell membrane serotonintransporter Na+-coupledcell membrane dopamine transporter NHHO NH3+HOHOH2CCH2NH3+cytosoloutsidemajor targets for drugs of therapy and abusePresynapticterminalsFrom Lecture 5Trademarks:11from Lecture 5:Could cells utilize plasma membrane H+ fluxes? Probably not.There are not enough protons to make a bulk flow, required for robustly maintaining the ion concentration gradients.(but some very small organelles (~ 0.1 m) do indeed store energy as H+ gradients).12NeurotransmitterandATP(1,000 to 10,000 molecules of each)3. Proton-coupled neurotransmitter transporter cytosol2. ATP-driven proton pump H+cytosolcytosolH+transmitter~ isotonic!How synaptic vesicles fill from the cytosolvesicle interiorvesicle interior13NeurotransmitterandATPkinesincell bodypresynapticterminal~ 20 distinct proteinsvesicle transport;pumping protons;pumping neurotransmitter; docking;fusion;recycling.cytosol50 nmLecture 10Synaptic vesicles have many proteins14NeurotransmitterandATP(1,000 to 10,000 molecules of each)proton-coupled vesicularneurotransmitter transporter cytosolATP-driven proton pump pH effects also account for some drug actions on synaptic vesiclesHNCH3OH2COCH33,4-methylenedioxymethamphetamine(MDMA, “ecstasy”, XTC) pKa ~ 8.515proton-coupledvesicular serotonin transporter cytosolATP-driven proton pump synaptic cleftNa+-coupledcell membrane serotonin transporterMDMAserotonin vesicleMDMAMDMA-H+H+MDMA (“ecstasy”) dissipates the vesicle’s H+ store, preventing the vesicle from pumping serotoninserotonin depletedserotonin vesicleMDMA-H+Weak acids and weak bases short-circuit many vesicles!16These proteins have evolved in a natural—perhaps necessary--way to provide that•The resting potential arises via selective permeability to K+This selective permeability also leads to the Nernst potential. Transient breakdowns in membrane potential are used as nerve signals.•Neuronal and non-neuronal cells also signal via transient influxes of Na+ and Ca2+.3 classes of proteins that transport ions across membranes:Little Alberts 12-4© Garland Ion channels that flux many ions per eventIon-coupled transporters“Active” pumps that split ATPfrom Lecture 517How does the electric field across a biological membrane compare with other electric fields in the modern world?1. A “high-voltage” transmission line1 megavolt = 106 V.The ceramic insulators have a length of ~ 1 m.The field is ~ 106 V/m. 2. A biological membraneThe “resting potential” ~ the Nernst potential for K+, 60 mV.The membrane thickness is ~ 3 nm = 30 A.The field is (6 x 10-2 V) / (3 x 10-9 m) = 2 x 107 V/m!Dielectric breakdown voltages (V/m)Ceramic 8 x 107Silicone Rubber 3 x 107Polyvinyl chloride 7 x 106from Lecture 6:Introduction to Voltage-Gated Channels18K+ ions lose their waters of hydration and are co-ordinated by backbone carbonyl groups when they travel through a channel.H2OK+ ioncarbonylFrom Lecture 519H2OK+ ioncarbonylFrom Lecture 5As of 13 April 2006, there are no crystal structures of voltage-gated Na+ and Ca2+ channels. But the similarities in sequence allow us to assume that the secondary and tertiary structures resemble those of K+ channels. A voltage-gated Na+ channel can be changed to a voltage-gated Ca2+ channel by mutating . . .just 2 out of 1800 amino acids20docked vesiclenerve impulsevoltage-gated Ca2+ channelneurotransmitterElectricity, then chemistry triggers synaptic vesicle fusion21voltage-gated Ca2+ channelElectricity, then chemistry triggers synaptic vesicle fusionCa2+docked vesicleneurotransmitternerve impulse22fused vesicleCa2+neurotransmitterElectricity, then chemistry triggers synaptic vesicle fusion23A conotoxin:25 amino acidsheld together by disulfide bondsindividual conotoxins specifically block individual ion channelsThis conotoxin blocks Ca2+ channels.Slightly modified, it is now the drug, ziconotide.It suppresses transmission at pain synapses in the spinal cord.(Swiss-prot viewer must be installed on your