Neurotransmitter Systems PDF

CHAPTER 6 NEUROTRANSMITTER SYSTEMS INTRODUCTION Three classes of neurotransmitters Amino acids, amines, and peptides Many different neurotransmitters Defining particular transmitter systems By the molecule, synthetic machinery, packaging, reuptake...

CHAPTER 6 NEUROTRANSMITTER SYSTEMS INTRODUCTION Three classes of neurotransmitters Amino acids, amines, and peptides Many different neurotransmitters Defining particular transmitter systems By the molecule, synthetic machinery, packaging, reuptake and degradation, etc. Acetylcholine (Ach) First identified neurotransmitter Nomenclature (-ergic) Cholinergic and noradrenergic  STUDYING NEUROTRANSMITTER SYSTEMS Neurotransmitter - three criteria Synthesis and storage in presynaptic neuron Released by presynaptic axon terminal Produces response in postsynaptic cell Mimics response produced by release of neurotransmitter from the presynaptic neuron TRANSMITTER-GATED CHANNELS Introduction Fast synaptic transmission Sensitive detectors of chemicals and voltage Regulate flow of large currents Differentiate between similar ions G-PROTEIN- COUPLED RECEPTORS Three steps Binding of the neurotransmitter to the receptor protein Activation of G-proteins Activation of effector systems The Basic Structure of G-Protein-Coupled Receptors (GPCRs) Single polypeptide with seven membrane-spanning alpha-helices The Ubiquitous G-Proteins GTP-binding (G-) protein Signalà from receptor to effector proteins  G-PROTEIN- COUPLED RECEPTORS Five steps in G-protein operation Inactive: Three subunits - a, b, and g - “float” in membrane (a bound to GDP) Active: Bumps into activated receptor and exchanges GDP for GTP Ga-GTP and Gbg - Influence effector proteins Ga inactivates by slowly converting GTP to GDP Gbg recombine with Ga-GDP GPCR Effector Systems The Shortcut Pathway From receptor to G-protein to ion channel; Fast and local G-PROTEIN-COUPLED RECEPTORS GPCR Effector Systems Second Messenger Cascades G-protein: Couples neurotransmitter with downstream enzyme activation Slower in action cAMP AS A SECONDARY MESSENGER DAG AND IP3 AS SECONDARY MESSENGERS SIGNAL TRANSDUCTION: AMPLIFICATION NEUROTRANSMITTER CHEMISTRY CHOLINERGIC (ACH) NEURONS CHOLINERGIC (ACH) NEURONS Basal Forebrain Nucleus basalis Medial septal nucleus Nucleus of diagonal band Project to hippocampus, amygdala and cerebral cortex Learning and memory Loss leads to Alzheimer's disease Pedunculopontine nucleus and laterodorsal tegmental nucleus Project to reticular formation and thalamus Arousal and sleep/wake cycle NICOTINIC ACH RECEPTOR Non-selective ionotropic cation channels that generate excitatory post synaptic responses Needs two ACH molecules to bind to function Can bind nicotine (euphoria, relaxation, addiction) Snake venom (ɑ-bungarotoxin) binds and closes channel, leading to paralysis (in muscles) Receptor has five subunits Each subunit has large extracellular region and four membrane spanning domains Opening of channel leads to ACH effects (skeleton muscle contraction, fine tuning of function of neurons throughout visceral motor system of the CNS, leading to attention and arousal) MUSCARINIC ACH RECEPTORS Muscarine (poisonous alkaloid found in some mushrooms) Metabotropic receptor Mediate most effects of ACh in brain Only one ACh needed to bind Found in corpus striatum where they activate K+ channels to exert inhibitory influence on dopamine mediated motor effects Found in hippocampus where they close K+ channels and can lead to excitatory synaptic transmission Mediate peripheral cholinergic responses of autonomic effector organs (heart, smooth muscle, exocrine glands) Inhibit heart rate by vagus nerve innervation mAChR blockers useful clinically Atropine-used to dilate pupil Scopolamine-prevents motion sickness Ipratropium-useful in asthma  GLUTAMATE Most important transmitter for normal brain function Nearly all excitatory neurons in CNS are glutamatergic More than half of all brain synapses release glutamate Precursor is Glutamine Taken up by System A transporter 2 Glutaminase key enzyme Removed from synapse by Excitatory Amino Acid Transporters Glutamate-Glutamine Cycle with Glial Cells AMPA RECEPTOR Ionotropic glutamate receptor cation channel ɑ-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate Allows passage of Na+ and K+ Produces excitatory postsynaptic responses EPSCs larger and faster than other glutamate receptors Tetramer NMDA RECEPTOR Ionotropic glutamate receptor Unique pore allows Na+, K+ AND Ca2+ entry Excitatory postsynaptic potentials increases Ca2+ (which can act as secondary messenger) Mg2+ blocks the pore when cell is hyperpolarized Imparts unique voltage dependence to current flow through the receptor Remove Mg2+ removes this behavior Pass cations only when postsynaptic membrane potential is depolarized (need both glutamate and postsynaptic depolarization to open) May represent some form of synaptic information storage and synaptic plasticity Also requires co-agonist glycine for gating METABOTROPIC GLUTAMATE RECEPTORS Three classes of exist Can lower postsynaptic responses that can excite or inhibit postsynaptic cells Many lead to inhibition of postsynaptic Ca2+ and Na+ channels GABA Inhibitory neurotransmission ˠ-aminobutyric acid One third of synapses use GABA Most found in local circuit interneurons as well as in the striatum, and cerebellar Purkinje cells Glucose converted to glutamate (TCA cycle); glutamate converted to GABA via glutamic acid decarboxylase Need pyridoxal phosphate for synthesis; comes from vitamin B6 Transported into vesicles via vesicular inhibitory amino acid transporter (VIAAT) Removal involves Na+ dependent co transporters and breakdown in glial or neurons to succinate GABA RECEPTORS GABAA Ionotropic anion channel (mainly Cl-) Pentamer; 19 subunit types Pore is lined with positive charged amino acids Benzodiazepines (Valium; anxiety) enhance opening of channel Hypnotics (Ambien; sleep) enhance opening of channel Barbiturates (pentobarbital; anesthesia and epilepsy) enhance opening of channel Ethanol binds and alters ionotropic GABA receptor activity GABAB Metabotropic and inhibitory Activates K+ channels Blocks Ca2+ channels GLYCINE Half of inhibitory synapses in spinal cord Synthesized from serine by serine hydroxymethyltransferase Transported into vesicles via vesicular inhibitory amino acid transporter (VIAAT) Removed from synapse by glycine transporters IONOTROPIC GLYCINE RECEPTORS Pentamer Ligand gated Cl- channels Influx of Cl- inhibits postsynaptic neuron Blocked by strychnine (toxic alkaloid chemical in some plants)  BIOGENIC AMINES: CATECHOLAMINERGIC NEURONS DOPAMINE Mesostriatal Pathway Substantia nigra-striatum (putamen and caudate nucleus) Coordination of body movements Defective in substantia nigra in Parkinson’s disease (leads to motor dysfunction) Mesolimbocortical Pathway Ventral Tegmental Area-amygdala, nucleus accumbens, cortex, hippocampus (Rewards Pathway) Motivation, Reward, Reinforcement Produced by DOPA decarboxylase from DOPA Loaded into vesicles via vesicular monoamine transporter (VMAT) Terminated by reuptake in neuron or glia via Na+ dependent dopamine co- transporter (DAT) Cocaine inhibit Amphetamines inhibit Monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) break down dopamine Activates metabotropic Dopamine receptors Act by either activating or inhibiting adenylyl cyclase  NOREPINEPHRINE Noradrenaline Synthesized within locus coeruleus (brainstem) Project to cerebral cortex, thalamus, pons, cerebellum, and spinal cord Influences mood, sleep, wakefulness, arousal, attention, feeding, and sexual behavior Requires dopamine β hydroxylase Produces norepinephrine from dopamine Loaded into vesicles via VMAT Cleared by norepinephrine transporter (NET) Degraded by MAO and COMT Acts on ɑ and β adrenergic receptors G protein coupled receptors EPINEPHRINE Adrenaline Found at lower levels than other catecholamines Lateral tegmental system and in medulla (project to thalamus and hypothalamus) Regulate respiration and cardiac function Produced by Phenylethanolamine-N-methyltransferase Loaded into vesicles by VMAT Acts on ɑ and β adrenergic receptors HISTAMINE Found in hypothalamic connections to all regions of brain and spinal cord Tuberomammillary nucleus of hypothalamus Mediate arousal and attention Controls reactivity of the vestibular system May influence brain blood flow Produced from histidine via histidine decarboxylase Transported into vesicles via VMAT Can be taken up by monoamine transporter Degraded by histamine methyltransferase and MAO Four histamine receptors All metabotropic receptors Many antagonists exist (basis of antihistamine agents (Benadryl) SEROTONIN 5-hydroxytryptamine (5-HT) Pons and upper brainstem with projections to forebrain Raphe nuclei (brainstem)-cortex, thalamus, hypothalamus, cerebellum Regulate anxiety, mood, sleep, and wakefulness Target for numerous antipsychotic drugs (depression and anxiety) Synthesized from tryptophan (tryptophan-5-hydroxylase) Loaded into vesicles by VMAT Signaling terminated by Specific Serotonin Transporter (SERT) Target of many SSRIs (Prozac, Fluoxetine, Zoloft) Degraded by MAO 5 HT RECEPTORS Most are metabotropic Implicated in regulation of circadian rhythms, motor behaviors, emotional states, and mental arousal Impairments implicated in depression, anxiety disorders, schizophrenia LSD (lysergic acid diethylamide) causes hallucinations by activation of receptors Also mediate satiety and decreased food consumption, which is why certain serotonergic drugs are useful in eating disorders One group (5-HT3) are ligand gated ion channels Nonselective cation channel (excitatory PSP) Targets for Kytril and Zofran (used to prevent postoperative nausea) ATP AND PURINES ATP found in all synaptic vesicles Co-transmitter Excitatory in motor neurons of spinal cord, sensory and autonomic ganglia, possibly in hippocampus Ionotropic purinergic receptors P2X receptors Nonselective cation channel Excitatory PSPs Mechanosensation and pain Metabotropic purinergic receptors A2A adenosine target of caffeine (antagonist) May be responsible for stimulant effects of coffee! NEUROPEPTIDES Hormones that act as neurotransmitters Pre-propeptides first formed in soma ER Signal sequence removed to form propeptide Moves to Golgi and packaged into vesicle Further modifications (cleavage, glycosylation, phosphorylation, disulfide bond formation) Grouped into five categories Brain-Gut peptides Opioid peptides Pituitary peptides Hypothalamic releasing hormones ”All Other” Peptides Virtually all receptors mediated through G protein coupled receptor  SUBSTANCE P Brain Gut Peptide Hypotensive agent 11 amino acid peptide Hippocampus, neocortex, and gastrointestinal tract Conveys information about pain and temperature Spinal Cord Sensory neurotransmitter Inhibited by opioid peptides (pain suppression) OPIOID PEPTIDES Bind to same postsynaptic receptors activated by opium (analgesic) One opium poppy main ingredient is morphine Discovered in 1970s when looking for endorphins (endogenous compounds mimicking actions of morphine) More than 20 opioid peptides discovered in three classes Endorphins Enkephalins Dynorphins Depressants in the CNS Most likely involved in sexual attraction, aggressive and submissive behaviors May be involved in psychiatric disorders (schizophrenia and autism) Fentanyl Selective agonist of opioid receptors 80X analgesic potency of morphine ENDOCANNABINOIDS Unconventional Neurotransmitter Interact with cannabinoid receptors Target of Δ9-tetrahydrocannabinol Unsaturated fatty acids Produced in post synaptic neurons through rise in Ca2+ Terminated by carrier mediated transport back to postsynaptic neuron Hydrolyzed by fatty acid hydrolase CB1 Receptors Metabotropic receptor Synaptic regulation in hippocampus and cerebellum Inhibit GABA release from presynaptic membrane