Unformatted text preview: Small molecule neurotransmi/ers • Acetylcholine • Purines (ATP) • Amino acids Glutamate • Aspartate • GABA • Glycine Biogenic amines • Dopamine • Norepinephrine • Epinephrine • Serotonin • histamine Two families of postsynapAc receptors • ionotropic‐ligand gated ion channels • metabotropic receptors‐ depends on one or more metabolic steps. • Do not have ion channels as part of their structure. Instead acAvate channels through messengers, called G‐proteins. Also called G‐protein coupled receptors. • Give rise to PSPs with diﬀerent Ame courses. Ionotropic receptors are fast, G‐protein coupled receptors are slow. • Some neurotransmi/ers use both types Metabotropic receptors Ligand binding site G‐protein binding site Acetylcholine • The neurotransmi/er used at the neuromuscular juncAon. Also used at synapses in visceral motor system and at some CNS synapses‐ called cholinergic neurons. • Synthesized from acetyl CoA and choline by choline acetyl transferase (CAT)‐its presence is a good indicaAon that the neuron is cholinergic. • Removed from synapse by acetylcholine esterase (AChE) has high acAvity can cleave 5000 molecules per second • Sarin “nerve gas” is a AChE inhibitor Acetylcholine AChE Inhibition Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare. Designed to be dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain. Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death. These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm. Cholinergic receptors • Best studied‐ the nicoAnic ACh receptor (nAChR) • Pentamer‐5 subunits to make a pore. SelecAve for caAons. • NicoAne can mimic ACh to sAmulate receptor, this is called an agonist. Most eﬀects of nicoAne go through this receptor. NicoAne is not cleared very well so receptor stays open longer which leads to larger EPSPs • all nACh receptors produce EPSPs. • Many toxins speciﬁcally bind to and block nicoAnic receptors called antagonists. • alpha‐bungarotoxin (snake venom)‐ binds to alpha subunit of nAChR very Aghtly and prevents ACh from acAvaAng it. Green is motor axons, red is where Bungarotoxin binds, deﬁnes the endplates Structure of the nACh receptor • 5 subunits come together to make a pore. • each subunit has 3‐4 membrane spanning domains. • In muscles the receptor has 2 α, β,γ,ε subunits. The α subunits bind ACh, both need to be bound for channel to open. α subunits also binds bungarotoxin and nicoAne. • MulAple isoforms for each subunit, depending on which isoform is in channel get diﬀerent properAes • In neurons its slightly diﬀerent. 5 subunits 3α:2β bungarotoxin only inhibits muscle nACh receptors. Muscle nAChR • Pentamers of 2α1, ß1, γ, δ in fetal mammals vs. 2α1, ß1, δ, ε in adult mammal • ACh, nico=ne, curare, and bungarotoxin binding sites are on the α1 subunits Pore size 10x bigger than Na channels (3 nm vs .3 nm) Ligand Gated Ion Channels
Built up of 4 or 5 monomers Each monomer spans the membrane 3 or 4 times Each monomer contributes properties Mixing and matching from a large pool of monomer isoforms creates receptors with different properties Muscarinic ACh receptors muscarinic ACh receptors • mACh‐ muscarine, a poisonous mushroom alkaloid, is an agonist. • Metabotropic, mediates most of ACh eﬀects in the brain. • 5 or so isoforms • mACh blockers are used for pupil dilaAon (atropine), moAon sickness (scopolamine) and asthma treatment (ipratropium). • Also used for bad things h/p://www.rense.com/general38/frug.htm Glutamate Most important transmi/er for normal brain funcAon. Nearly all excitatory neurons in the CNS are glutamatergic. Does not cross the blood brain barrier. Glutamine is most common precursor. Glutaminase converts it to glutamate. • Retrieved from synapse by glutamate transporters in glia and neurons. Glia turn glutamate to glutamine and spit it back out • Too much glutamate can kill the post‐synapAc neuron‐ called exitotoxicity. A major problem a^er damage due to stroke. • • • • Glutamate Glutamate receptors • Both ionotropic and metabotropic • ionotropic‐ NMDA receptors, AMPA receptors, and kainate receptors‐named a^er the agonists that sAmulate them. • all are non‐selecAve caAon channels with Erev close to 0 (above threshold therefore excitatory). • Formed from an associaAon of many subunits, that can combine to create many isoforms AMPA/Kainate receptors • glutamate receptors that allow Na or K ions across. • mulAsubunit channels • evoke EPSPs that are large and fast • Generally a synapse will contain all three types at once. NMDA receptor • Allow ﬂow of Ca as well as Na and K. As a result EPSPs produced by NMDA receptors can increase Ca concentraAon in the neuron. Acts as a second messenger to acAvate cellular processes. • Needs a co‐agonist, glycine to open channel • Blocked by Mg2+ in the pore during hyperpolarizing condiAons. DepolarizaAon can remove block. Needs either a bunch of presynapitc cells to ﬁre at the same Ame or repeated ﬁring of presynapAc cell to open channel • A model for learning. • evoke EPSPs that are slow and long lasAng • PCP “angel dust” binds and clogs channel. Get symptoms similar to schizophrenia. Some hypothesis NMDA receptor is involved in this disease. NMDA receptor currents require glycine and removal Of a Mg block. outward inward • Glycine is a co‐agonist‐no glycine no current. • Mg blocks pore‐is removed by depolariza=on. • This can happen if AMPA and Kainate receptors are in the same area. NMDA and AMPA / kainate Receptors fast on fast oﬀ slow on slow oﬀ combo metabotropic glutamate receptors mGluRs • large class of receptor subtypes • G‐protein coupled • SomeAmes inhibitory someAmes excitatory GABA and Glycine • Most inhibitory neurons use one or the other. • Inhibits the ability to ﬁre acAon potenAals. • GABA made from glutamate by glutamic acid decarboxylase (GAD), requires Vitamin B6 as cofactor. B6 deﬁciency can lead to loss of synapAc transmission. • Glycine‐ about 1/2 of neurons in spinal cord use glycine. • Both GABA and glycine are rapidly take up by glia and neurons. • Hyperglycinemia‐ defect in glycine uptake and removal‐leads to severe mental retardaAon. Glycine • Inhibitory neurotransmiIer – makes the post‐synapAc membrane more permeable to Cl‐ hyperpolarizes the membrane – glycine receptor is primarily found in the ventral spinal cord • Strychnine
• glycine antagonist which can bind to the receptor without opening the Cl-channel • (i.e. it inhibits inhibition) • spinal hyperexcitability Synthesis, Release, and Reuptake of the Inhibitory Neurotransmi/ers GABA and Glycine Synthesis, Release, and Reuptake of the Inhibitory Neurotransmi/ers GABA and Glycine GABA receptors • Three types of GABA receptors A,B and C. • A and C are ionotropic, B is metabotropic. • A and C are inhibitory because their channels are permeable to Cl‐. The ﬂow of Cl‐ into the cell lowers the potenAal. Erev is less than threshold potenAal. • pentamers, subunit diversity as well as variable stoichiometry, allows for variable funcAons of GABA receptors. • Glycine receptors have generally the same properAes as GABA receptors Ionotrophic GABA Receptors current due to many channels opening step nature shows individual channels closing. Examples of GABA receptor-mediated IPSPs recorded at different membrane potentials Reversal potential is at the Nernst potential for Cl- ions. (In this case about –78 mV) Figure from Coombs et al. 1955) The GABA receptor binds many interesAng things Biogenic amines • Catacholamines‐ dopamine, norepinerphrine and epinephrine • Histamine • Serotonin • All catacholamines derived from tyrosine, tyrosine hydroxylase rate limiAng step and good marker for catacholaminergic neurons • Are implicated in many complex behaviors The BiosyntheAc Pathway for the Catecholamine Neurotransmi/ers • PN06111.JPG The BiosyntheAc Pathway for the Catecholamine Neurotransmi/ers • PN06112.JPG Synthesis of Histamine and Serotonin • PN06132.JPG dopamine • Produced by the enzyme DOPA decarboxylase • Made by substancia nigra and projects to corpus striatum (coordinaAon of body movements). • Does not cross the blood brain barrier, but levadopa does. • Parkinsons treatments include L‐dopa plus degradaAon enzyme inhibitors • Cocaine inhibits uptake of dopamine PET scans before and a^er cocaine before a^er Red means lots of unoccupied dopamine receptors norepinephrine • Comes from dopamine by way of dopamine‐B hydroxylase. • SympatheAc gangilion cells use it‐project to visceral motor system‐ﬁght or ﬂight response. • used as a transmi/er in locus coeruleus‐in brainstem‐projects to areas that are involved in sleep, a/enAon, and feeding. • its reuptake mechanism , the norepinepherine transporter (NET) is a target of amphetamines. The DistribuAon of Neurons in the Human Brain Containing Biogenic Amines epinephrine • adrenaline‐present at lower levels than the others. • made by neurons in rostro medulla‐project to thalamus and hypothalamus. The exact funcAon of epinephrine secreAng neurons is not known. Catecholamine Receptors • Act exclusively by acAvaAng G‐protein coupled receptors. Contribute to complex behaviors. • NE and epinephrine each act on α and β adrenergic receptors. serotonin 5‐hydroxy tryptamine (5‐HT). made from tryptophan reuptake by speciﬁc seratonin transporters many anAdepressants act by inhibiAng serotonin reuptake (selecAve serotonin reuptake inhibitors‐SSRIs). Prozac. • Found primarily in groups of neurons in the raphe region of the pons and upper brainstem. • The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness. • • • • histamine • Made from hisAdine, metabolized by monoamine oxidase • Made by neurons in hypothalamus that send projecAons to all regions of the brain and spinal cord. • Mediates arousal and a/enAon. • Histamine receptors are in the immune system and in the CNS. The sedataAve side aﬀects of Benedryl act through the CNS. Synthesis of Histamine and Serotonin • PN06131.JPG • PN06122.JPG The DistribuAon of Neurons in the Human Brain Containing Biogenic Amines Serotonin receptors • Large family of receptors called 5‐HT 1‐7. • 5‐HT3 is a ligand gated non‐selecAve caAon channel, thus it is excitatory. • Same basic structure as nACh receptor. • All others are metabotropic‐likely perturbaAons in these receptors are involved in many neural disorders. ATP and other purines • • • • ATP is contained in all synapAc vesicles Has speciﬁc receptors on post‐synapAc cells Generally exciAtory in nature Used in spinal cord, motor neurons and other ganglia. Purinergic receptors • Widely distributed in the nervous system • 3 classes‐ one class is ligand‐gated ion channel. Two classes are GPCR. • Ion channels‐ non‐selecAve caAon channel, excitatory. Diﬀerent protein structure than the other guys. Have only 2 tm domain subunits. A lot of their funcAon is unknown. • Two types of metabotropic receptors‐ one type preferenAally sAmulated by adenosine the other sAmulated by ATP. PepAde neurotransmi/ers • 3‐36 or so amino acids, cleaved from larger precursor proteins • catabolized by pepAdases • 5 general classes, brain/gut pepAdes, opoid pepAdes, pituitary pepAdes, hypothalamic releasing hormones, all others. • Packaged into large dense core vesicles (amino acids are packaged into small clear core vesicles). • Generally used as co‐transmi/ers ProteolyAc Processing of the Pre‐PropepAdes, Pre‐ ProopiomelanocorAn and Pre‐Proenkaphalin ACTH‐adrenocorAcotripic hormone‐ modulaAon of pain ProteolyAc Processing of the Pre‐PropepAdes, Pre‐ ProopiomelanocorAn and Pre‐Proenkaphalin opoid pepAdes Clear core vesicles release upon a single acAon potenAal Large core release a^er mulAple acAon potenAals Examples of pepAde neurotransmi/ers • Substance P, 16 amino acid pepAde • present in human hippocampus, neocortex, and gi tract (hence a brain‐gut pepAde) • Involved in the percepAon of pain • Released from C‐ﬁbers which carry informaAon about pain Opioids • Bind to same post‐synapAc receptors as opium. • Family with more than 20 members, three basic groups: endorphins, enkephalins, and dynorphins. • O^en co‐localized with GABA and serotonin • Tend to act as depressants, used for analgesics. • Repeated use o^en leads to tolerance and addicAon PepAde receptors • Virtually all mediate their eﬀects by acAvaAng G‐protein coupled receptors. • NPY receptor important in obesity • Opiate receptors have been idenAﬁed and shown to be important in addicAon. FuncAonal Features of the Major Neurotransmi/ers • PN06T11.JPG FuncAonal Features of the Major Neurotransmi/ers • PN06T12.JPG summary • Neurotransmi/er receptors bind neurotransmi/ers‐ tremendous diversity‐ with commonaliAes. • Two types‐ ionotropic (ligand‐gated ion channel) and metabotropic (G‐protein coupled receptor). • Both types lead to opening or closing of ion channels. These conductance changes can either increase or decrease the probability of ﬁring an acAon potenAal. • Because postsynapAc neurons are usually innervated by many diﬀerent inputs, it is the combinaAon of EPSP and IPSPs that determines whether a cell ﬁres and an acAon potenAal occurs. ...
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- Fall '09