lecture 8

lecture 8 - Two families of postsynap0c receptors...

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Unformatted text preview: Two families of postsynap0c 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 ac0vate channels through messengers, called G ­proteins. Also called G ­protein coupled receptors. •  Give rise to PSPs with different 0me courses. Ionotropic receptors are fast, G ­protein coupled receptors are slow. •  Some neurotransmiCers use both types Metabotropic receptors Ligand binding site G ­protein binding site Small molecule neurotransmiCers •  Acetylcholine Amino acids •  •  •  •  Glutamate Aspartate GABA Glycine •  Purines (ATP) Biogenic amines •  •  •  •  •  Dopamine Norepinephrine Epinephrine Serotonin histamine Acetylcholine •  The neurotransmiCer used at the neuromuscular junc0on. 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 indica0on that the neuron is cholinergic. •  Removed from synapse by acetylcholine esterase (AChE) has high ac0vity can cleave 5000 molecules per second •  Sarin “nerve gas” is a AChE inhibitor Acetylcholine AChE Inhibition" Ⱥ  Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare. Ⱥ  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. Ⱥ  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 nico0nic ACh receptor (nAChR) •  Pentamer ­5 subunits to make a pore. Selec0ve for ca0ons. •  Nico0ne can mimic ACh to s0mulate receptor, this is called an agonist. Most effects of nico0ne go through this receptor. Nico0ne 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 nico0nic receptors called antagonists. •  alpha ­bungarotoxin (snake venom) ­ binds to alpha subunit of nAChR very 0ghtly and prevents ACh from ac0va0ng it. Green is motor axons, red is where Bungarotoxin binds, defines the endplates 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 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 nico0ne. •  Mul0ple isoforms for each subunit, depending on which isoform is in channel get different proper0es •  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) 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 dila0on (atropine), mo0on sickness (scopolamine) and asthma treatment (ipratropium). •  Also used for bad things hCp://www.rense.com/general38/frug.htm Glutamate Most important transmiCer for normal brain func0on. 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 ­synap0c 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 s0mulate them. •  all are non ­selec0ve ca0on channels with Erev close to 0 (above threshold therefore excitatory). •  Formed from an associa0on of many subunits, that can combine to create many isoforms AMPA/Kainate receptors •  glutamate receptors that allow Na or K ions across. •  mul0subunit channels •  evoke EPSPs that are large and fast •  Generally a synapse will contain all three types at once. NMDA receptor •  Needs a co ­agonist, glycine, to open channel •  Blocked by Mg2+ in the pore during hyperpolarizing condi0ons. Depolariza0on can remove block. Needs either a bunch of presynapitc cells to fire at the same 0me or repeated firing of presynap0c cell to open channel •  Allow flow of Ca as well as Na and K. As a result EPSPs produced by NMDA receptors can increase Ca concentra0on in the neuron. Acts as a second messenger to ac0vate cellular processes. •  evoke EPSPs that are slow and long las0ng •  A model for learning. •  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 •  Some0mes inhibitory some0mes excitatory GABA and Glycine •  Most inhibitory neurons use one or the other. •  Inhibits the ability to fire ac0on poten0als. •  GABA made from glutamate by glutamic acid decarboxylase (GAD), requires Vitamin B6 as cofactor. B6 deficiency can lead to loss of synap0c 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 retarda0on. Glycine •  Inhibitory neurotransmiIer –  makes the post ­synap0c 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 NeurotransmiCers GABA and Glycine Synthesis, Release, and Reuptake of the Inhibitory NeurotransmiCers 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 poten0al. Erev is less than threshold poten0al. •  pentamers, subunit diversity as well as variable stoichiometry, allows for variable func0ons of GABA receptors. •  Glycine receptors have generally the same proper0es 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 interes0ng things Biogenic amines •  Catacholamines ­ dopamine, norepinephrine and epinephrine •  Histamine •  Serotonin •  All catacholamines derived from tyrosine, tyrosine hydroxylase rate limi0ng step and good marker for catacholaminergic neurons •  Are implicated in many complex behaviors The Biosynthe0c Pathway for the Catecholamine NeurotransmiCers •  PN06111.JPG The Biosynthe0c Pathway for the Catecholamine NeurotransmiCers •  PN06112.JPG dopamine •  Produced by the enzyme DOPA decarboxylase •  Made by substancia nigra and projects to corpus striatum (coordina0on of body movements). •  Does not cross the blood brain barrier, but levadopa does. •  Parkinsons treatments include L ­dopa plus degrada0on 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. •  Sympathe0c gangilion cells use it ­project to visceral motor system ­fight or flight response. •  used as a transmiCer in locus coeruleus ­in brainstem ­projects to areas that are involved in sleep, aCen0on, and feeding. •  its reuptake mechanism , the norepinepherine transporter (NET) is a target of amphetamines. The Distribu0on 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 func0on of epinephrine secre0ng neurons is not known. Catecholamine Receptors   Act exclusively by ac0va0ng 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 an0depressants act by inhibi0ng serotonin reuptake (selec0ve 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. •  •  •  •  Synthesis of Histamine and Serotonin Serotonin receptors •  Large family of receptors called 5 ­HT 1 ­7. •  5 ­HT3 is a ligand gated non ­selec0ve ca0on channel, thus it is excitatory. •  Same basic structure as nACh receptor. •  All others are metabotropic ­likely perturba0ons in these receptors are involved in many neural disorders. histamine •  Made from his0dine, metabolized by monoamine oxidase •  Made by neurons in hypothalamus that send projec0ons to all regions of the brain and spinal cord. •  Mediates arousal and aCen0on. •  Histamine receptors are in the immune system and in the CNS. The sedata0ve side affects of Benedryl act through the CNS. Synthesis of Histamine and Serotonin ATP and other purines •  •  •  •  ATP is contained in all synap0c vesicles Has specific receptors on post ­synap0c cells Generally exci0tory 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 ­selec0ve ca0on channel, excitatory. Different protein structure than the other guys. Have only 2 tm domain subunits. A lot of their func0on is unknown. •  Two types of metabotropic receptors ­ one type preferen0ally s0mulated by adenosine the other s0mulated by ATP. Pep0de neurotransmiCers •  3 ­36 or so amino acids, cleaved from larger precursor proteins •  catabolized by pep0dases •  5 general classes, brain/gut pep0des, opoid pep0des, pituitary pep0des, hypothalamic releasing hormones, all others. •  Packaged into large dense core vesicles (amino acids are packaged into small clear core vesicles). •  Generally used as co ­transmiCers Proteoly0c Processing of the Pre ­Propep0des, Pre ­ Proopiomelanocor0n and Pre ­Proenkaphalin ACTH ­adrenocor0cotripic hormone ­ modula0on of pain Proteoly0c Processing of the Pre ­Propep0des, Pre ­ Proopiomelanocor0n and Pre ­Proenkaphalin opoid pep0des Clear core vesicles release upon a single ac0on poten0al Large core release a^er mul0ple ac0on poten0als Examples of pep0de neurotransmiCers •  Substance P, 16 amino acid pep0de •  present in human hippocampus, neocortex, and gi tract (hence a brain ­gut pep0de) •  Involved in the percep0on of pain •  Released from C ­fibers which carry informa0on about pain Opioids •  Bind to same post ­synap0c 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 addic0on Pep0de receptors •  Virtually all mediate their effects by ac0va0ng G ­protein coupled receptors. •  NPY receptor important in obesity •  Opiate receptors have been iden0fied and shown to be important in addic0on. Func0onal Features of the Major NeurotransmiCers Func0onal Features of the Major NeurotransmiCers summary •  NeurotransmiCer receptors bind neurotransmiCers ­ tremendous diversity ­ with commonali0es. •  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 ac0on poten0al. •  Because postsynap0c neurons are usually innervated by many different inputs, it is the combina0on of EPSP and IPSPs that determines whether a cell fires and an ac0on poten0al occurs. ...
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This document was uploaded on 02/28/2011.

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