Click here to load reader

Neurotransmission - Tocris Bioscience ... Tocris Product Guide Series 2 | Neurotransmission Research Contents Introduction Neurotransmission, or synaptic transmission, refers to the

  • View
    0

  • Download
    0

Embed Size (px)

Text of Neurotransmission - Tocris Bioscience ... Tocris Product Guide Series 2 | Neurotransmission Research...

  • Neurotransmission

    Contents by Research Area: • Dopaminergic Transmission • Glutamatergic Transmission • Opioid Peptide Transmission • Serotonergic Transmission • Chemogenetics

    Delphinium Delphinium A source of Methyllycaconitine

    Product Guide | Edition 1

  • Tocris Product Guide Series

    2 |

    Neurotransmission Research

    Contents

    Introduction Neurotransmission, or synaptic transmission, refers to the passage of signals from one neuron to another, allowing the spread of information via the propagation of action potentials. This process is the basis of communication between neurons within, and between, the peripheral and central nervous systems, and is vital for memory and cognition, muscle contraction and co-ordination of organ function. The following guide outlines the principles of dopaminergic, opioid, glutamatergic and serotonergic transmission, as well as providing a brief outline of how neurotransmission can be investigated in a range of neurological disorders.

    Included in this guide are key products for the study of neurotransmission, targeting different neurotransmitter systems. The use of small molecules to interrogate neuronal circuits has led to a better understanding of the under- lying mechanisms of disease states associated with neurotransmission, and has highlighted new avenues for treat- ment. Tocris provides an innovative range of high performance life science reagents for use in neurotransmission research, equipping researchers with the latest tools to investigate neuronal network signaling in health and disease. A selection of relevant products can be found on pages 23-33.

    Page

    Principles of Neurotransmission 3

    Dopaminergic Transmission 5

    Glutamatergic Transmission 6

    Opioid Peptide Transmission 8

    Serotonergic Transmission 10

    Chemogenetics in Neurotransmission Research 12

    Depression 14

    Addiction 18

    Epilepsy 20

    List of Acronyms 22

    Neurotransmission Research Products 23

    Featured Publications and Further Reading 34

    Key Neurotransmission Research Products

    Box Number Title Page

    Box 1 Dopaminergic Transmission 5

    Box 2 Glutamatergic Transmission 7

    Box 3 Opioid Transmission 9

    Box 4 Serotonergic Transmission 11

    Box 5 Chemogenetic Compounds: DREADD ligands and PSEMs

    13

    Box Number Title Page

    Box 6 Antidepressants 15

    Box 7 Ketamine and its Metabolites 17

    Box 8 Addiction 19

    Box 9 Epilepsy 20

  • NEUROTRANSMISSION RESEARCH

    www.tocris.com | 3

    Principles of Neurotransmission The majority of neurotransmission occurs across chemical syn- apses, where an endogenous neurotransmitter is released by the presynaptic neuron and detected by receptors on the post- synaptic neuron (Figure 1). Neurotransmitters can be broadly split into three categories; amino acids including glutamate and glycine, amines including dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and peptides such as dynorphin, the enkephalins and neuropeptide Y.

    While the amino acids glutamate and glycine are found in all cells of the body, other neurotransmitters are only synthe- sized by neurons. Following synthesis, neurotransmitters are taken up and stored in synaptic vesicles, ready for release. The release of a neurotransmitter is triggered by the arrival of action potentials in the axon terminal of the presynaptic neuron, open- ing voltage-gated Ca2+ channels and allowing influx of ions. The resulting elevation in intracellular Ca2+ concentration causes synaptic vesicles to merge with the presynaptic mem- brane, releasing the neurotransmitter into the synaptic cleft by exocytosis.

    Neurotransmitters cross the synaptic cleft and bind to their spe- cific receptors. These maybe ligand-gated ion channels (LGICs) or G protein-coupled receptors (GPCRs), with some neuro- transmitters having receptors in both categories. Binding of a neurotransmitter to a LGIC causes a conformational change in the structure of the protein, allowing the passage of ions through the channel. Passage of ions through channels that are selective for positively-charged cations results in depolariza- tion of the postsynaptic membrane and initiation of an action potential in the postsynaptic neuron. In contrast, passage of ions through negatively-charged, anion selective channels results in hyperpolarization of the postsynaptic membrane, so inhibiting action potential initiation. Binding of a neuro- transmitter to a GPCR results in the activation of G proteins, which are then able to act on enzymes to modulate intracellular signaling pathways. The end result of this is the modulation of activity of other proteins, including ion channels and enzymes.

    Once a neurotransmitter has bound to its receptor, it is cleared from the synaptic cleft to allow another wave of synaptic

    This simplified schematic shows the main events during dopaminergic, glutamatergic, opioid peptide and serotonergic neurotransmission. DA and 5-HT are both biogenic amines that are derived from amino acids, while glutamate itself is an amino acid and opioid peptides are cleaved from precursor proteins. All neurotransmitters undergo exocytosis from the presynaptic membrane and cross the synaptic cleft where they bind to their specific receptors. These receptors may be ligand gated ion channels, such as ionotropic glutamate receptors, or G protein-coupled receptors, such as all subtypes of opioid receptor. Passage of ions through a ligand gated ion channel alters the excitability of a neuron. The action of neurotransmitters at GPCRs alters intracellular signaling pathways, with the specific pathway being dependent on the G protein-coupled to the receptor.

    Figure 1 | Principles of Neurotransmission

    Presynaptic neuron Postsynaptic neuron

    Precursor proteins

    Opioid proteins

    Glu

    Glu

    Gi/0

    Gs

    AC

    cAMP

    ATP

    PLC

    Mg2+

    5-HT3

    NMDARs

    AMPARs and Kainate receptors

    5-HT1,5 D2,3,4

    Opioid receptors Group II and III mGluRs

    IP3

    Ca2+

    Ca2+

    Na+

    CaMK

    CaMK

    Increased neuronal

    excitability

    DAG PKC

    PKA

    Gq/11

    PDE (–)

    (–)

    (–)

    5-HT

    DA

    DAT

    SERT

    5-HT4,6,7 D1.5

    5-HT2 Group I mGluRs

  • Tocris Product Guide Series

    4 |

    Detected in immersion-fixed paraffin- embedded sections of human brain (substantia nigra) using a Goat Anti-Human/ Mouse/Rat DDC Antigen Affinity-Purified Polyclonal Antibody (R&D Systems, Cat. No. AF3564). The tissue was stained using the Anti-Goat HRP-DAB Cell & Tissue Staining Kit (R&D Systems, Cat. No. CTS008; brown) and counterstained with hematoxylin (blue. Tocris, Cat. No. 5222). Specific staining was localized to the neuronal cytoplasm.

    D1R detected in immersion-fixed paraffin- embedded sections of human brain (caudate nucleus) using a Mouse Anti-Human Dopamine D1R Monoclonal Antibody (R&D Systems, Cat. No. MAB8276). The tissue was stained using the Anti-Mouse HRP-DAB Cell & Tissue Staining Kit (R&D Systems, Cat. No. CTS002; brown) and counterstained with hematoxylin (blue. Tocris, Cat. No. 5222). Specific staining was localized to the neuronal cytoplasm.

    DAT1 detected in immersion-fixed sections of human brain (substantia nigra) using a Mouse Anti-Human/Mouse/Rat DAT1 Monoclonal Antibody (Novus Biologicals, Cat. No. NBP2-46649). The tissue was stained using HRP and DAB (brown) and counterstained with hematoxylin (blue. Tocris, Cat. No. 5222). Specific staining was localized to the dopamine neuron nuclei and fibres.

    Figure 2 | DDC in Human Brain Figure 3 | D1R in Human Brain Figure 4 | DAT1 in Human Brain

    transmission. Neurotransmitter molecules are taken up by the presynaptic neuron, or by other cell types such as astrocytes, via specific reuptake transporters. Neurotransmitters may then be metabolized to be reused for further production, or they can be recycled into synaptic vesicles.

    The strength of the synaptic connection between two neurons depends on a range of factors. These include the number of individual synapses between two neurons, the probability of neurotransmitter release at the presynaptic membrane and the size of the post-synaptic potential induced by binding of the neurotransmitter to its receptor. The presence of neurotrans- mitter receptors on the pre-synaptic membrane also regulates the release of neurotransmitters, through both positive and negative feedback loops. Synaptic connection strength is a key factor in cognitive processes including memory formation.

    Action Potentials

    An action potential is the signal that conveys information along a neuron and is also the trigger for release of a neurotrans- mitter at a synapse. Physically, an action potential is the rapid reversal of the resting membrane potential, caused by opening and closing of voltage-gated ion channels. At rest, the cytosol of a neuron is negatively charged (polarized) with respect to extracellular fluid, due to the distribution of ions across the cell membrane.

    An action potential is initiated by the opening of voltage-gated Na+ channels (Nav channels) allowing influx of Na+ down its

    concentration gradient. This depolarizes the cell membrane past the threshold for action potential initiation. As Nav chan- nels become inactivated, preventing the flow of Na+, voltage- gated potassium channels (Kv channels) open allowing t

Search related