Neurotransmitter Systems Chapter 6 PDF

Neurotransmitter Systems Chapter 6  – Discuss the criteria neurotransmitters have to meet – Learn about the experimental methods that allow us to study whether neurotransmitters meet those criterion – Understand the main categories of neurotrans...

Neurotransmitter Systems Chapter 6  – Discuss the criteria neurotransmitters have to meet – Learn about the experimental methods that allow us to study whether neurotransmitters meet those criterion – Understand the main categories of neurotransmitters Learning and their functions – Discuss the difference between transmitter-gated ion objectives channels and G-protein-coupled receptors – To frame things: we’ll be talking about exactly what a neurotransmitter *is*, how we figured that out, and how it generally works in the nervous system  – Neurotransmitters are chemical keys that open receptor(protein) locks. – Three classes of neurotransmitters – Amino acids, amines, and peptides – Many different neurotransmitters, each sending a different “message” Overview of – Defining particular transmitter systems neurotransmitter – By the molecule, synthetic machinery, packaging, reuptake systems and degradation, and action – Acetylcholine (Ach) – First identified neurotransmitter – Nomenclature (-ergic) – Cholinergic and noradrenergic  – A molecule can be called a neurotransmitter if it meets these 3 How can you tell criteria / if you can prove the molecule is: 1. Synthesized and stored in presynaptic neuron if something is a 2. Released by presynaptic axon terminal distinct 3. When applied extraneously/”artificially”, mimics postsynaptic neurotransmitter cell response produced by “natural” release of neurotransmitter from the presynaptic neuron ?  – There are several techniques to localize transmitters and transmitter- synthesizing enzymes within certain neurons: – Immunocytochemistry—localize molecules to cells using antibodies Studying neurotransmitter systems  – There are several techniques to localize transmitters and transmitter- synthesizing enzymes within certain neurons: – Immunocytochemistry—localize molecules to cells using antibodies Studying neurotransmitter systems  – There are several techniques to localize transmitters and transmitter- synthesizing enzymes within certain neurons: – In situ hybridization—Localize synthesis of protein or peptide to a cell (detect mRNA) Studying neurotransmitter systems  – Transmitter candidate: synthesized and localized in terminal and released upon stimulation – Determined through immunocytochemistry & in situ hybridization – CNS contains a diverse mixture of synapses that use different neurotransmitters – how do you isolate one? – Brain slices are used as a model. Studying – Kept alive in vitro à stimulate synapses, collect and measure released chemicals neurotransmitter – New methods such as optogenetics allow us to turn on specific systems synapses!  – Qualifying condition: Molecules evokes same response as neurotransmitter. – Microiontophoresis : assess postsynaptic Studying actions – Apply tiny amount of neurotransmitter neurotransmitter externally & study effects systems – Microelectrode: measures effects on membrane potential from the chemical that was added  – Neuropharmacological analysis also tells us a lot about the actions of neurotransmitters – Agonists and antagonists – ACh receptors – Nicotinic, muscarinic – Glutamate receptors – AMPA, NMDA, and kainate Studying neurotransmitter systems  – Neuropharmacological analysis also tells us a lot about the actions of neurotransmitters – Agonists and antagonists – ACh receptors – Nicotinic, muscarinic – Glutamate receptors – AMPA, NMDA, and kainate Studying neurotransmitter systems  – Ligand-binding methods – Identify natural receptors using radioactive ligands – visual analysis of receptor localization – Ligand can be agonist, antagonist, or chemical neurotransmitter. – Example: opiate receptors Studying neurotransmitter systems  – Molecular analysis—receptor protein classes – Transmitter-gated ion channels – GABA receptors – 5 subunits, each made with 6 different subunit polypeptides – G-protein-coupled receptors Studying neurotransmitter systems  – Evolution of neurotransmitters – Neurotransmitter molecules – Amino acids, amines, and peptides – Ach is an exception – it’s a special chemical derived from the mitochondria during cellular respiration – Dale’s principle – more common – A neuron has only one neurotransmitter. – Co-transmitters – less common Neurotransmitter – Two or more transmitters released from one nerve terminal – An amino acid or amine plus a peptide chemistry  – Acetylcholine (ACh) is the neurotransmitter found at Cholinergic neuromuscular junctions – All cholinergic neurons contain (ACh) an enzyme called choline acetyltransferase (ChAT), which neurons is required to synthesize ACh – ChAT is therefore a good way to mark cholinergic cells  – Catecholiminergic neurotransmitters are powerful (tyrosine is precursor) – Involved in movement, mood, attention, and visceral function – Tyrosine: precursor for three amine neurotransmitters that contain catechol group Cate- – Dopamine - parkinsons – Norepinephrine cholaminergic – Epinephrine (adrenaline) neurons  – Serotonin (5-HT) producing neurons are called serotonergic – Amine neurotransmitter Serotonergic – Derived from tryptophan (5-HT) – Regulates mood, emotional behavior, sleep neurons – Selective serotonin reuptake inhibitors (SSRIs)—antidepressants – Melatonin is derived from serotonin  – Glutamate, glycine, and GABA – Differences among amino acidergic neurons are quantitative, not qualitative. – Glutamic acid decarboxylase Amino (GAD) – Key enzyme in GABA synthesis acidergic – Good marker for GABAergic neurons neurons – GABAergic neurons are major source of synaptic inhibition in the CNS. – Whatever is made more is what takes the name  – ATP excites some neurons, Other neuro- binds to purinergic receptors. transmitter – Endocannabinoids – Retrograde messengers candidates & – These molecules don’t meet the extracellular criteria for being called neurotransmitters (yet?) messengers  – Fast synaptic transmission – Sensitive detectors of chemicals and voltage – Regulate flow of large currents – Differentiate between similar ions Transmitter- gated ion channels  – The basic structure of transmitter-gated channels – Pentamer: 5 protein subunits form a pore – Example: nicotinic Ach receptor at neuromuscular junction Transmitter- gated ion channels  – The basic structure of transmitter-gated channels – Pentamer: 5 protein subunits form a pore – Example: nicotinic Ach receptor at neuromuscular junction Transmitter- gated ion channels  – Amino acid-gated channels mediate most of the fast synaptic transmission in the CNS – They are pretty ubiquitous – Glutamate-gated channels – Mediate synaptic excitation – AMPA, NMDA, kainite Transmitter- – Some are voltage-dependent gated ion – Voltage-dependent NMDA channels channels  – Amino acid-gated channels mediate most of the fast synaptic transmission in the CNS – They are pretty ubiquitous – GABA-gated and glycine-gated channels – GABA mediates most synaptic inhibition in CNS. – Glycine mediates non-GABA synaptic inhibition. Transmitter- – Bind ethanol, benzodiazepines, barbiturates (“depressants”) gated ion channels  – G-protein-coupled receptors have three steps in transmission – Binding of the neurotransmitter to the receptor protein ( has g- protein tag) – Activation of G-proteins – Activation of effector systems – Basic structure of G-protein-coupled receptors (GPCRs) G-protein- – Single polypeptide with 7 membrane-spanning alpha-helices coupled receptors & effectors  – G-protein-coupled receptors have three steps in transmission – Binding of the neurotransmitter to the receptor protein – Activation of G-proteins – Activation of effector systems – Basic structure of G-protein-coupled receptors (GPCRs) G-protein- – Single polypeptide with 7 membrane-spanning alpha-helices coupled receptors & effectors G-protein- – G-protein is short for guanosine triphosphate (GTP) binding protein coupled – There are many different types but they are all called G-proteins receptors & – Signal à from receptor to effector proteins effectors  1. Inactive: 3 subunits—a, b, and g—“float” in membrane (a bound to GDP) 2. Active: bumps into activated receptor and exchanges GDP for GTP G-protein 3. Ga-GTP and Gbg—influence effector operation proteins steps 4. Ga inactivates by slowly converting GTP to GDP. 5. Ga and Gbg recombine to start the cycle again.  – There are two ways the G-protein- G-protein- coupled receptor can ultimately bring about a change in the postsynaptic coupled neuron; one is a “shortcut” way and one is more complex effector – The “shortcut” pathway systems – From receptor to G-protein to ion channel—fast and localized  – There are two ways the G-protein-coupled receptor can ultimately bring about a change in the postsynaptic neuron; one is a “shortcut” way and one is more complex – Second messenger cascades – the more complex (but powerful) G-protein- way – G-protein: couples neurotransmitter with downstream enzyme coupled activation effector systems  – There are two ways the G-protein-coupled receptor can ultimately bring about a change in the postsynaptic neuron; one is a “shortcut” way and one is more complex – Second messenger cascades – the more complex (but powerful) way G-protein- – G-protein: couples neurotransmitter with downstream enzyme activation coupled – Push–pull method (different G-proteins stimulate or inhibit adenylyl cyclase) effector systems  – There are two ways the G-protein-coupled receptor can ultimately bring about a change in the postsynaptic neuron; one is a “shortcut” way and one is more complex – Second messenger cascades – the more complex (but powerful) way – G-protein: couples neurotransmitter with downstream enzyme activation – Push–pull method (different G-proteins stimulate or inhibit adenylyl G-protein- cyclase) coupled – Some cascades branch into even more paths – G-protein activates PLC, generates DAG and IP3 activate different effector effectors systems  – Some key words to know for G-protein-coupled receptor/effector system functionality: – Phosphorylation and dephosphorylation – Phosphate groups added to or removed from a protein G-protein- – Changes conformation and biological activity coupled effector systems  – Some key words to know for G- protein-coupled receptor/effector system functionality: G-protein- – Signal amplification – This is kind of the whole point coupled of using G-protein-coupled effector systems – As the signals cascade down, systems they become amplified / stronger – Exponential increase-like effect  – Some key words to know for G- protein-coupled receptor/effector G-protein- system functionality: – Divergence coupled – One transmitter activates more than effector one receptor subtype à greater postsynaptic response systems – Convergence – Different transmitters converge to affect same effector system.  – Neurotransmitters – Transmit information between neurons – Essential link between neurons and effector cells Why do we care – Signaling pathways so much about – Signaling network within a neuron somewhat resembles brain’s neural network. neurotransmitter – Inputs vary temporally and spatially to increase and/or systems? decrease drive. – Delicately balanced – Signals regulate signals—drugs can shift the balance of signaling power. Quiz hint! – Categories of neurotransmitters A note about – Would y’all be ok having class in CSHP 223? – (Anatomy & physiology lab) next class – I have brain models in that classroom y’all can work with.  – It’s 1 week from today – I recommend you begin studying now! A note about – Neuroanatomy is very memorization-heavy so it’s in your best interest to get the conceptual stuff down early so you have your first energy for memorization. neuro exam – Format will be multiple choice, true/false, and short answer questions – 40 combined MC + T/F (2 pts each) – 4 short answer (5 pts each) Questions?