COGNITIVE SCIENCE 107A Neurotransmitters Jaime A. Pineda, Ph.D.
Exocytosis
~20 Amino Acids Used for Protein Synthesis Non-essential (Our bodies can make them) Alanine (A) Arginine (R) Asparagine (N) Aspartate (D) Cysteine (C)* Glutamate (E) Glycine (G)* Glutamine (Z)* Proline (P)* Serine (S)* Tyrosine (Y)* Essential (body cannot make them must get from diet) Histidine (H)* Isoleucine (I) Leucine (L) Lysine (K) Methionine (M) Phenylalanine (F) Threonine (T) Tryptophan (W) Valine (V) * Essential only in certain cases
Making Proteins DNA sequences Transcription/Translation
RECEPTORS Ionotropic Metabotropic
Ionotropic Form a channel Metabotropic
Ionotropic Receptor (agonist)
Ionotropic Receptors 1. Work very fast; important role in fast neurotransmission 2. Each is made of several subunits (together form the complete receptor) 3. At center of receptors is channel or pore to allow flow of neurotransmitter 4. At rest - receptor channels is closed 5. When neurotransmitter bind -- channel immediately opens 6. When ligand leaves binding site -- channel quickly closes
Metabotropic Receptors 1. Work more slowly than ionotropic receptors 2. Though it takes longer for postsynapic cell to respond, response is somewhat longer-lasting 3. Comprise a single protein subunit, winding back-and-forth through cell membrane seven times (transmembrane domains) 4. They do not possess a channel or pore
Metabotropic Receptor
(leads to opening of channel)
Changes to Postsynaptic Receptor Density as a Function of the Amount of Neurotransmitter Released Upregulation Downregulation
Reasons for a chemical signaling system Greater degree of amplification and control Increased computational capability Lengthens the time of cellular integration from ms to minutes and even hours Allows neurons to respond differently as a function of preceding activity Allows the system to be sensitive to behavioral states Allows for brain circuits to be multifunctional
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Slide 4 of 46 Endocrine Cell
Neurohormone Neurohormone Slide 6 of 46
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Neuron Via synaptic connection Slide 5 of 46 Neuron
GAP JUNCTIONS: ELECTRICAL SYNAPSES
Criteria for a Neurotransmitter Must be synthesized and released from neurons. Appropriate biochemical machinery must exist in the presynaptic neuron. Must be released in response to an electrical signal. Should produce a physiological response in the postsynaptic target. Postsynaptic effects should be blocked by known antagonists of the transmitter in a dose-dependent manner Appropriate mechanisms must exist to terminate the action of the neurotransmitter Chemical deactivation Recapture (endocytosis) Glial uptake diffusion
Classes of Neurotransmitters Amino Acids fast +/- Glutamate and GABA Biogenic Amines Acetylcholine, Dopamine, Norepinephrine, Serotonin Neuropeptides Endorphins Others Lipids, gases slow +/-/modulatory
Glutamate Principal excitatory NT Biosynthesized as byproduct of glucose metabolism (Krebs cycle) Removed by reuptake (neuronal/glia) Can be neurotoxic 4 receptor types NMDA AMPAa Ionotropic Kainate AMPAb Metabotropic
NMDA Binding Sites 4 outside cell Glutamate Glycine Obligatory co-agonist Inhibitory NT at its own receptor Zinc (inverse agonist) Polyamine (indirect agonist/antagonist) 2 inside cell Magnesium (inverse agonist) PCP (inverse agonist)
NMDA Receptor Detects simultaneous events ( AND gate; molecular coincidence detector) Gated by combination of voltage and ligand Glu + Gly opens channel to Ca ++, Magnesium (Mg ++ ) block removed by membrane depolarization Mediates learning and memory via LTP (long term potentiation) Involved in process of addiction; behavioral sensitization, and drug craving
GABA (Gamma Aminobutyric Acid) Principal Inhibitory NT Biosynthesis: Glu Glutamic Acid Decarboxylase (GAD) and B6 GABA Removed by reuptake and enzymatically by GABA-oxoglutarate transaminase (GABA-T) 2 receptor types GABA A (ionotropic) controls Cl- channel GABA B (metabotropic; autoreceptor)- controls K+ channel
GABA GABAa Binding Sites Muscimol (direct agonist); bicuculine (direct antagonist) Benzodiazepine (indirect agonist) Natural inverse agonist binds here (fear, tension, anxiety) Tranquilizing drugs (anxiolytics): valium, librium Likely site for alcohol Barbiturate (indirect agonist) Phenobarbital; pentobarbital Steroid (indirect agonist) Picrotoxin (inverse agonist): causes convulsions
GABAergic Drugs Agonists Benzodiazepines Barbiturates Ethyl alcohol (ETOH) Ro15-4513, a GABA a antagonist (indirect for GABA, direct for alcohol) reverses alcohol intoxication Antagonists Picrotoxin Inverse agonist Ro 15-4513
Acetylcholine (most abundant NT in PNS) Mostly excitatory effects Synthesis: Removal: Acetyl CoA + Choline Choline Acetyltransferase (ChAT) CoA + ACh Ach Acetylcholine Esterase (AChE) Acetate + Choline 2 receptor types Nicotinic (ionotropic) Muscarinic (metabotropic)
Monoamines Catecholamines Dopamine - DA Dopaminergic Norepinephrine - NE Noradrenergic Epinephrine - E Adrenergic ~ Tyrosine L-DOPA DA NE E TH AADC DBH PNMT Indolamines Serotonin - 5-HT Serotonergic Tryptophan 5-HT melatonin TH TH-tyrosine/tryptophan hydroxylase AADC-aromatic acid decarboxylase or DOPA decarboxylase DBH-dopamine beta hydroxylase PNMT-phenylethanolamine N-methyltransferase
Monoamines (DA, NE, 5-HT) Modulatory (can have both excitatory and inhibitory effects- varies by receptor) Recycled by reuptake transporter Excess NT in terminal broken down by monoamine oxidase (MAO A/B ) catechol-o-methyltranferase - COMT Axonal varicosities (bead-like swellings) with both targeted and diffuse release
Indirect Monoamine Agonists MAOIs Iproniazid Reuptake blockers Tricyclic antidepressants Imipramine Desipramine - SSRIs Cocaine & Amphetamine ~
Dopamine Reward, motivation, cognition, memory, learning, and fine motor control, and modulation of neuroendocrine signaling Biosynthesis: Tyrosine L-DOPA DA Tyrosine Hydroxylase DOPA Decarboxylase Dopamine reuptake transporter (DAT) 5 receptor types (D1 D5, all metabotropic) D1 (postsynaptic) activate camp D2 (pre autoreceptors and postsynaptic) Autoreceptors are release-regulating homeostatic mechanisms inhibit camp
Major DA Pathways Nigrostriatral (Substantia Nigra Striatum) [Motor movement] Mesolimbic (VTA limbic system) [Reinforcement and Addiction] Mesocortical (VTA prefrontal cortex) [Working memory and planning]
Norepinephrine Arousal, attention, stress Biosynthesis: DA Dopamine Beta-hydroxylase NE DBH found in vesicles (released with neurotransmission) Norepinephrine reuptake transporter (NET) Many receptor types (metabotropic) α 1, β 1-2 (postsynaptic, excitatory) α 2 (autoreceptor, inhibitory)
Major NE Pathway Locus Coeruleus throughout brain [vigilance and attentiveness]
Serotonin Mood, eating, sleep/dreaming arousal, pain, aggression (social cognition) Biosynthesis: Tryptophan 5-HTP 5-HT Tryptophan Hydroxylase 5-HT Decarboxylase Similar structure as LSD; serotonin reuptake transporter (SERT) At least 9 receptor types, all metabotropic and postsynaptic except: 5-HT 1A,B,D (autoreceptors) subordinates; 5-HT2 dominant 5-HT 3 (inhibitory, ionotropic)
Major 5-HT Pathways Dorsal Raphe Nuclei cortex, striatum Medial Raphe Nuclei cortex, hippocampus
Serotonergic Drugs Agonists SSRIs Selective Serotonin Reuptake Inhibitors MDMA Ecstacy ~ Antagonists Psilocybin LSD
Opioids: General Genetically coded, synthesized from mrna as prohormones (slow response to increased demand) Biosynthesis in cell body; large vesicles (100 nm) Colocalized with and modulate effects of other neurotransmitters Act as neurotransmitters and neuromodulators Released by repetitive stimulation or burst firing Broken down by enzymes (no reuptake); metabolites can be biologically active Usually modulatory/inhibitory
Why so many neuropeptides? Afferent convergence on a common neuron To distinguish multiple inputs (chemical coding) Colocalization No reuptake mechanisms may mean more nonsynaptic release
Opioids: Specific β-endorphin made from proopiomelanocortin (POMC) produced in pituitary gland, hypothalamus, brain stem Enkephalin (met- and leu-) made from proenkephalin (PENK) produced throughout brain and spinal cord Dynorphin made from prodynorphin (PDYN) produced throughout brain and spinal cord
Opioids Receptors Receptor High affinity ligands Mu (1,2) β-endorphin, enkephalins Delta enkephalins Kappa dynorphins Omega Opioids act at all opioid receptors, but with different affinities Distributed throughout brain and spinal cord, especially in limbic areas Some overlap but quite distinct localizations
Opioid Receptors continued Metabotropic, with either moderately fast indirect action on ion channels long-term action via changes in gene expression Most analgesic effects from mu receptor action Some analgesic effects from delta Many negative side effects from kappa
Other (Unconventional) NTs Do not meet the criteria for a neurotransmitter yet seem to be important for communication Growth factors Brain derived neurotrophic gactor (BDNF) Nitric Oxide (NO) - It s a gas Carbon Monoxide (CO) and hydrogen sulfide Not stored in vesicles Anandamide ligand for THC-R ~