Lecture 5 - Neurotransmitters PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 5 of 24 – Neurotransmitters (first half of chapter 4, pp. 103-116) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  RECEPTOR PROTEINS Recep...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 5 of 24 – Neurotransmitters (first half of chapter 4, pp. 103-116) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  RECEPTOR PROTEINS Receptor A protein that is sensitive to a stimulus and passes along the message. protein It can be a neurotransmitter receptor or a receptor for something else (e.g., smell, taste, touch, light, etc.) All receptors are either ionotropic or metabotropic. Ionotropic A receptor that is an ion channel. Receptor Its activation has an immediate consequence on the cell’s membrane potential - causing an EPSP (depolarization and more spiking) or - causing an IPSP (hyperpolarization and less spiking) depending on whether the pore of the ion channel is permeable to Na+ or Cl- Metabotropic A receptor that is not an ion channel. receptor It typically triggers an intracellular signaling cascade involving g proteins. Metabotropic receptor activation can have large or small effects on any cellular process, but the effects won’t be instantaneous, since they depend on intracellular signaling and diffusion. All g protein-coupled receptors (GPCRs) are metabotropic receptors. Metabotropic Receptors G-protein signaling cascades can affect diverse cellular processes, such as: opening ion channels changing gene expression secretion of substances cell growth cell division (not in neurons) cell death anything the cell wants  Metabotropic Receptor? G Proteins? “–tropic” means “turn toward”. Ionotropic receptors turn toward ions to mediate their effect. Metabotropic receptors turn toward metabolism to mediate their effects. o Metabolism refers to “chemical reactions within cells”. Metabotropic receptors trigger intracellular signaling cascades that catalyze chemical reactions. o Most metabotropic receptors mediate their effects by activating g proteins. o The name “g protein” symbolizes that these proteins use GTP molecules, instead of ATP, for the energy they need to catalyze a chemical reaction. o G proteins are molecular switches. When bound to GTP, they are “ON” or activated. In this state, they can catalyze chemical reactions. The ON state can last between 10 seconds and several minutes depending on the g protein. The ON state is temporary because g proteins have a natural tendency to convert GTP to GDP, causing them to become “OFF” or inactivated. o G proteins have a hard time letting go of GDP. They need an activated metabotropic receptor to do so. In the OFF state, they will stand next to a metabotropic receptor and wait for it to become activated. When that happens, the g protein can let go of their GDP molecule. They will then rapidly find a new molecule of GTP and become ON again. Metabotropic Receptor Signaling Activation cycle of g proteins (in pink/purple) Step 1: The cycle starts when a ligand (brown) finds a metabotropic receptor (light blue). Ligand binding to a metabotropic receptor (2) induces a conformational change that helps the g protein let go of GDP (3), allowing it to bind a molecule of GTP (4). Then the g proteins diffuse away to trigger chemical reactions (5). At some point the g protein will convert GTP to GDP (6). It will then go back to the metabotropic receptor and wait (1). Some ion channels are gated by g proteins. They are called g protein-gated ion channels. To open these ion channels… 1) a signaling molecule has to activate a metabotropic receptor, 2) allowing a g-protein to become activated. 3) The activated g protein can bind (directly or indirectly) to a g-protein-gated ion channel. A top-down view of postsynaptic membrane, illustrating how the activation of two metabotropic receptors (blue) can cause the opening of eight g-protein-gated ion channels (green). Most synapses contain both ionotropic and metabotropic receptors. Even if only one neurotransmitter (like glutamate) is ever released into that synapse, the postsynaptic membrane is likely to contain both ionotropic and metabotropic glutamate receptors. WHERE CAN SYNAPSES FORM? Synapses can form between an axon terminal and … 1) smooth dendrite (a dendritic shaft) 2) a dendritic spine These locations are well-positioned to generate an action potential 3) a soma (cell body) 4) another axon terminal (axoaxonic synapse)  AXOAXONIC SYNAPSES Axoaxonic synapses regulate the amount of neurotransmitter that the second neuron (in red) will release when it has an action potential. Presynaptic inhibition Axoaxonic synapses can hyperpolarize the axon terminal of the downstream neuron (in red), so its voltage-gated calcium channels will not open as much as they normally do when the there is an action potential (in the red cell). The net effect is to reduce neurotransmitter release from the red cell when it has an action potential. Presynaptic facilitation Axoaxonic synapses can depolarize the axon terminal of the downstream neuron (in red), so that its voltage-gated calcium channels are more likely to open when an action potential arrives. The net effect is to increase neurotransmitter release from the red cell when it has an action potential. Autoreceptor: a receptor located on presynaptic membrane that makes the cell sensitive to its own neurotransmitter release. Postsynaptic receptor: receptor located on the Autoreceptors are gated by the receiving neuron (not on release of neurotransmitter the cell that is releasing from the cell they are in. the neurotransmitter). Autoreceptors are always metabotropic and inhibitory. They are the main source of presynaptic inhibition. End of material covered on the Quiz.  Neurotransmitters We give signaling molecules different names depending on where they are released and what they do. Signaling molecules released in the brain to regulate neural activity are called neurotransmitters. Signaling molecules released into the blood are called hormones. When dopamine is released in the brain, it is a neurotransmitter. When dopamine is released into the blood supply, it is a hormone. There are many different types of neurotransmitters. The four main categories are: 1. Classical, conventional neurotransmitters - glutamate, GABA, dopamine, serotonin, norepinephrine, acetylcholine 2. Neuropeptides - more than 70 different types 3. Lipid-based neurotransmitters - primarily the endocannabinoids 4. Gasotransmitters - primarily nitric oxide  Receptor Complexity Classical General General Neurotransmitters Receptor Type Effect Subtype Effect AMPA ionotropic excitatory GluR1-only excitatory NMDA ↑ ↑ GluR3-only ↑ Kainate ↑ ↑ GluR1/2 ↑ mGluR1 metabotropic ↑ GluR2/3 ↑ mGluR2 ↑ inhibitory Glutamate mGluR3 ↑ ↑ mGluR4 ↑ excitatory GABA mGluR5 ↑ inhibitory mGluR6 ↑ excitatory mGluR7 ↑ ↑ mGluR8 ↑ ↑ Dopamine 5-HT1 metabotropic inhibitory 5-HT2A excitatory Norepinephrine 5-HT2 ↑ excitatory 5-HT2B mixed Acetylcholine 5-HT3 ionotropic ↑ 5-HT2C excitatory Serotonin 5-HT4 metabotropic ↑ 5-HT5 ↑ inhibitory 5-HT6 ↑ excitatory 5-HT7 ↑ ↑ You do not need to know this information.  The Classical Neurotransmitters Classical Neurotransmitters Glutamate Main excitatory neurotransmitter (because all ionotropic glutamate receptors let sodium in) GABA Main inhibitory neurotransmitter (because all ionotropic GABA receptors let chloride in) Dopamine Norepinephrine Acetylcholine Main neuromodulators These neurotransmitters primarily act on metabotropic Serotonin receptors and tend to exert a modulatory influence on cell activity (in contrast to glutamate and GABA, which often cause fast EPSPs or IPSPs via their respective ionotropic receptors). The Classical Neurotransmitters More than 99.9% of neurons release one of these two neurotransmitters: Glutamate Typically excitatory (the gas pedal) Ionotropic glutamate receptors let in sodium ions, causing excitatory post-synaptic currents (EPSCs) and membrane depolarization Drugs that activate glutamate receptors often cause seizures and excitotoxicity Drugs that block glutamate receptors slow you down, like the dissociative anesthetics ketamine and PCP. GABA Typically inhibitory (the brakes) Ionotropic GABA receptors let in chloride ions, causing inhibitory post-synaptic currents (IPSCs) and membrane hyperpolarization Drugs that block GABA receptors often cause seizures Drugs that activate GABA receptors slow you down: sleeping pills, anticonvulsants, muscle relaxants, anesthetics, anti-anxiety (alcohol, barbiturates, benzodiazepines) In addition to glutamate or GABA, many neurons also co-release neuromodulators and/or neuropeptides.  Classical Neurotransmitters The 4 main neuromodulators (acetylcholine, dopamine, serotonin, and norepinephrine) are released from small collections of neurons that send their axons out widely. We call them neuromodulators because most of their receptors are g-protein coupled receptors, not ion channels they typically don’t produce immediate EPSPs or IPSPs (at least not in the CNS). they can diffuse short distances outside of the synapse and influence the activity of neighboring neurons. noradrenaline = norepinephrine (mostly used as a neurotransmitter in the CNS) adrenaline = epinephrine (mostly used as a hormone in the body) Neuromodulators in the rat brain Dopamine Serotonin Norepinephrine Acetylcholine (Noradrenaline) You do not need to know this information.  Types of Neurotransmitters Conventional neurotransmitters - modified amino acids (small molecules) The main players are glutamate, GABA, dopamine, serotonin, norepinephrine, and acetylcholine. synthesized locally in axon terminals packaged in small synaptic vesicles that dock close to the site of Ca2+ entry in the axon terminal recaptured and reused (via reuptake proteins) rarely leave the synapse (they sometimes travel to nearby neurons, but they do not get very far) have both ionotropic AND metabotropic receptors (dopamine and norepinephrine are exceptions to this rule) Neuropeptides – a small chain of amino acids (basically a protein that is only 10-30 amino acids long) Examples from the list of >70: oxytocin, vasopressin, enkephalin, prolactin, NPY, ghrelin, CRH. synthesized in the cell body, then transported down the axon and released just once packaged in large dense core vesicles that dock a ways back from the site of Ca2+ entry in the axon terminal not recycled (no reuptake of them or their component parts) may diffuse long distances and exert action at a distance (non-synaptic communication) only have metabotropic receptors (there are no ionotropic receptors for neuropeptides) Lipid-based signaling molecules – fat soluble molecules (cut from the cell membrane) The main players are anandamide and arachidonoyl glycerol. synthesized and released on demand, as needed (the details are complicated) are not packaged in vesicles (they can pass through cell membranes if not attached to something) only have metabotropic receptors signal backwards (they are released from postsynaptic membrane and the receptors are on axon terminals) Neurotransmitter Classification When classifying a neurotransmitter, we ask… 1) What type of molecule is it? Is it a modified amino acid? A peptide? Something else? 2) How and where is it made? Is it made by enzymes in the axon terminal? Or is it made back in the cell body by translating RNA? 3) How does it get released? Is it packaged into vesicles? If so, what kind of vesicles? 4) What kind of receptors can it bind to? Both ionotropic and metabotropic receptors? Or only metabotropic receptors? 5) How does it get cleared away after it is release? Is it constrained to the synapse, or can it diffuse freely? Is it ever recycled and reused?  CONVENTIONAL NEUROTRANSMITTER RELEASE Classic targets for drugs and toxins include: the enzymes that synthesize neurotransmitters in the axon terminal the transporter proteins that package neurotransmitters into vesicles the vesicle release machinery proteins that sense calcium to regulate neurotransmitter release the proteins that clear neurotransmitters out of the synapse the receptors that neurotransmitters bind to All classical (conventional) neurotransmitters are made in axon terminals. The raw ingredients (single amino acids) and necessary enzymes (proteins) are in axon terminals. Once a neurotransmitter is made, it gets packaged into a synaptic vesicle by a vesicular transporter.  The Monoamine Neuromodulators Serotonin, dopamine, and norepinephrine have a similar chemical and three-dimensional structure. We call them the monoamines. They are released by different neurons, and they activate different receptors, but there is only one protein that packages them into synaptic vesicles: the vesicular monoamine transporter (VMAT). Due to their similarity, some drugs activate (or block) all of their receptors nonspecifically. Dopamine and norepinephrine are super similar to each other. We call them the catecholamines. These neurotransmitters are recycled (brought back into the axon terminal). There is a different reuptake transporter for each of them: SERT, DAT, NET.