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Biochemistry of Neurotransmission: A Type of Cell-Cell Signaling

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Title: Biochemistry of Neurotransmission: A Type of Cell-Cell Signaling


1
Biochemistry of Neurotransmission A Type of
Cell-Cell Signaling
  • Biochemistry is fun

2
Biochemistry of Cell Signaling
Fig. 19-1
3
Study Guide
  • Contrast resting, ligand-gated, voltage-gated,
    and signal-gated ion channels
  • How do voltage gated ion channels monitor the
    voltage?
  • What is the neurotransmitter at the vertebrate
    neuromuscular junction? The crayfish
    neuromuscular junction?
  • What is the chief excitatory neurotransmitter in
    the mammalian brain? The chief inhibitory
    neurotransmitter? What vitamin is required for
    the synthesis of the chief inhibitory brain
    neurotransmitter? What is the role of PyP in
    catecholamine synthesis? What is the role of
    tetrahydrobiopterin in second messenger synthesis
    (3 answers)?
  • How is the action of acetylcholine terminated?
    Serotonin?
  • What is Parkinson's disease, and what is the
    mechanism for its development? How is
    parkinsonism treated?
  • How are neurotransmitters released at the
    synapse? What proteins are involved? Name the
    calcium ion sensor
  • Describe the Otto Loewi experiment and explain
    its significance.
  • What is myasthenia gravis and what is the
    mechanism for its development?
  • Describe the molecular components and actions of
    G-proteins. How many transmembrane domains do
    receptors that interact with G-proteins possess?
  • What is the role of cyclic GMP in vision?

4
Overview
  • The human brain contains about 1012 neurons, and
    some neurons make 1000 connections
  • Dendrites, cell body, axon
  • The cell body contains the nucleus, and this is
    where almost all protein synthesis occurs
  • The cell body also contains nearly all of the
    lysosomes
  • Proteins and other molecules are transported from
    the nucleus via axoplasmic transport
  • Axons are long processes specialized for the
    conduction of action potentials
  • The nervous system also contains glial cells that
    support and nourish the neurons (Schwann cells in
    the peripheral nervous system)
  • Types of neurons sensory neurons, interneurons,
    motor neurons

5
Neuroanatomy
Fig. 19-2
6
Anatomy of the Neuron
  • Arrows indicate the direction of conduction of
    the action potential
  • A motor neuron typically has a single axon
  • The axon of the sensory neuron branches after it
    leaves the cell body
  • Both branches are structurally and functionally
    axons
  • The cell body is located in the dorsal root
    ganglion near the spinal cord

7
Signaling within the Neuron
  • The axon carries an electrical impulse called the
    action potential.
  • These move at speeds of 100 m/s
  • The action potential originates in the axon
    hillock
  • An axon can be 1 meter and longer (from spinal
    cord to the big toe)
  • Dendrites receive signals and convert them into
    small electric impulses and transmit them to the
    cell body

8
The Action Potential
  • AP transient depolarization of the membrane
    followed by repolarization to about 60 mV
  • Below 1 action potential every 4 msec
  • Invasion of the synapse results in release of
    neurotransmitter that bind to postsynaptic
    receptors and activate them
  • This can be excitatory (depolarization)
  • This can be inhibitory (hyperpolarization)

9
Synapses
  • Specialized Sites where neurons communicate with
    other cells
  • Neurons
  • Muscle cells
  • Endocrine cells
  • Types of synapses
  • Chemical (vast, vast majority)
  • Presynaptic cell contains vesicles
  • The neurotransmitter (NT) interacts with
    postsynaptic cell within 0.5 ms
  • Electrical (a curiosity)
  • Connected by gap junctions
  • The next slide illustrates various synapses
  • Hippocampal interneurons which makes about 1000
    synapses (orange red dots)
  • Electron micrograph of a CNS synapse

10
Synapses
11
The Action Potential and the Conduction of
Electric Impulses
  • An electric potential exists across the plasma
    membrane because of ion gradients
  • Resting potential is about 60 mV owing to the
    large number of open potassium channels
  • Voltage-gated channels allow the transmission of
    the electrical impulses
  • Action Potential
  • Na channels open allowing Na to enter the cell
    and depolarize it, then they close for a
    refractory period
  • K channels open permitting efflux of K which
    hyperpolarizes the membrane
  • As these channels close, the membrane returns to
    its resting potential

12
Ion Channels
  • (c, d) are located on dendrites and cell bodies
  • d is coupled to a NT receptor via a G-protein

13
Origin of the Resting Potential
  • Sodium pump or sodium/potassium ATPase generates
    these gradients
  • Na is extracellular
  • K is intracellular
  • A- represents protein
  • The open potassium channels and the potassium
    gradient are responsible for the resting potential

14
Myelination Increases the Velocity of Impulse
Conduction
  • Myelin is a specialized membrane
  • Derived from Schwann cells in the PNS
  • Derived from oligodendrocytes (glia) in CNS
  • Contains protein and lipid
  • Action potential jumps from node to node
    (saltatory conduction), and this greatly
    increases the velocity of AP conduction
  • Less energy is required to transmit an action
    potential in a myelinated nerve
  • More energy is required to transmit an action
    potential in unmyelinated nerves
  • Most nerves are myelinated

15
Myelin Sheath
  • (a) Myelinated peripheral nerve surrounded by a
    Schwann cell that produces the myelin
  • (b) Sciatic nerve axon is surrounded by a myelin
    sheath (MS)

16
Myelinated and Non-Myelinated Nerves in Dental
Pulp
17
Structure of a Peripheral Myelinated Axon
18
Saltatory Conduction from Node to Node
  • Saltatory refers to the jumping of the action
    potential from node to node
  • The nodes are the only regions along the axon
    where the axonal membrane is in direct contact
    with the extracellular fluid

19
Molecular Properties of Voltage-Gated Ion Channels
  • Voltage-gated K channels are assembled from four
    similar subunits, each of which has six
    membrane-spanning alpha helices and a nonhelical
    P segment that lines the ion pore 24 TM segments
    total
  • Voltage-gated Na and Ca2 channels are monomeric
    proteins containing four homologous domains each
    similar to a K channel subunit 24 TM segments
    total
  • The S4 alpha helix acts as a voltage sensor
  • Voltage-sensing alpha helices have a lysine or
    arginine every third or fourth residue outward
    movement toward the negative extracellular space
    in response to depolarization opens the channel
  • Voltage-gated K, Na, and Ca2 channel proteins
    contain cytosolic domains that move into the open
    channel thereby inactivating it
  • Non-voltage gated K channels and
    nucleotide-gated channels lack a voltage-sensing
    alpha helix, but otherwise their structures are
    very similar to the voltage-gated K channels

20
Transmembrane Structures of Gated Ion-Channel
Proteins
  • The voltage-gated K channel consists of four
    identical subunits and six transmembrane alpha
    helices
  • Helix 4 is the voltage sensor
  • cAMP and cGMP-gated ion channels are made of four
    identical subunits that lack a voltage sensor
  • These occur in the olfactory and visual systems,
    respectively

21
Voltage-gated Na Channel
  • All voltage-gated channels contain four
    transmembrane domains (each with 6 TM segments),
    and each domain contributes to the central pore
  • In the resting state, the gate obstructs the
    channel
  • There are four voltage-sensing alpha helices
    which have positively charged side chains every
    third residue
  • When the outside of the membrane becomes negative
    (depolarized) the helices move toward the outer
    plasma membrane surface causing a conformational
    change in the gate segment that opens the channel
    as shown in b
  • Shortly afterwards, the helices return to the
    resting position as shown in c
  • The channel inactivating segment (purple) moves
    into the open channel preventing further ion
    movement as shown in c

22
Structure and Function of the Voltage-gated Na
Channel
23
Transmembrane Structures of Gated Ion-Channel
Proteins
  • Voltage-gated Na and Ca channels are monomers
  • These form a channel similar to that of the K
    channel
  • There are 24 transmembrane segments
  • These channels contain regulatory portions, not
    shown here

24
Neurotransmitters (NTs)
  • Impulses are transmitted by the release of NTs
    from the axon terminal of the presynaptic cell
    into the synaptic cleft. NTs bind to specific
    receptors on the postsynaptic cell causing a
    change in the ion permeability and the potential
    of the postsynaptic plasma membrane
  • Classical NTs are imported from the cytosol into
    synaptic vesicles by a protein-coupled
    antiporter, a V-type ATPase that maintains a low
    intravesicular pH (V vesicle)
  • The V-type ATPase pumps protons into the synaptic
    vesicle
  • Then protons leave the vesicle in exchange for
    the NT which is transported inward this is
    antiport
  • Catecholamines (DA, NE, EPI) are unstable at pH
    7 they are stable at pH 5 in the intravesicular
    space
  • Excitatory receptors lead to depolarization
    thereby promoting generation of an action
    potential
  • Inhibitory receptors lead to hyperpolarization
    thereby inhibiting generation of an action
    potential
  • Ligand-gated receptors induce rapid (msec)
    responses

25
Neurotransmitters (cont)
  • G-protein coupled receptors (GPCR) induce
    responses that last for seconds or more
  • Removal of transmitters is by hydrolysis
    (metabolism), diffusion away from the synapse, or
    most commonly by uptake
  • ACh by hydrolysis
  • Nearly all other NTs by uptake
  • A single postsynaptic cell can amplify, modify,
    and compute excitatory and inhibitory signals
    received from multiple presynaptic neurons
  • Postsynaptic cells generate action potentials in
    an all-or-nothing fashion
  • At electric synapses, ions pass directly from the
    pre to the postsynaptic cell through gap
    junctions
  • Impulse transmission at chemical synapses occurs
    with a small time delay but is nearly
    instantaneous at electric synapses

26
Small Molecule Neurotransmitters
  • Acetylcholine (ACh)
  • Vertebrate neuromuscular junction
  • Pre and postganglionic parasympathetic nervous
    system
  • Preganglionic sympathetic nervous system
  • Central nervous system (CNS)
  • Glycine chief inhibitory NT in the spinal cord
  • Glutamate chief excitatory NT in the CNS
  • Dopamine (DA) selected CNS neurons parkinsonism
  • Norepinephrine (NE)
  • Postganglionic sympathetic NS
  • Selected CNS neurons

27
Small Molecule Neurotransmitters (cont)
  • Epinephrine
  • Selected CNS
  • Adrenal medulla
  • 5-Hydroxytryptophan (5-HT), or serotonin CNS
    (Prozac, Zoloft, SSRIs, selective serotonin
    reuptake inhibitors)
  • Histamine (mast cells)
  • GABA (gamma aminobutyric acid) chief inhibitory
    NT in the CNS

28
Selected Neurotransmitters
ACh at the vertebrate nm junction Glutamate at
the invertebrate nm junction (crayfish and
lobster)
29
Acetylcholine
  • Grandfather of all neurotransmitters
  • Sites of action
  • Vertebrate neuromuscular junction nicotinic
  • Pre-and post-ganglionic parasympathetic
    nicotinic and muscarinic, respectively
  • Pre-ganglionic parasympathetic nicotinic
  • Present in CNS (both Muscarinic and Nicotinic
    receptors)
  • Inactivated by hydrolysis (the only classical
    neurotransmitter that is inactivated by
    metabolism)
  • Pathology
  • Alzheimer (?)

30
Acetylcholine Metabolism (Fig. 19-15, 19-16)
  • ACh is inactivated by hydrolysis

31
Acetylcholine Congeners (Fig. 19-17)
32
Catecholamines
33
Catecholamine Biosynthesis
  • Tyrosine hydroxylase
  • First and rate-limiting
  • Activated by PKA and other PKs
  • Uses tetrahydrobiopterin as cofactor
  • Aromatic Amino Acid Decarboxylase (AAD) uses PyP
    (B6) as cofactor
  • Dopamine beta hydroxylase (DBH) uses vitamin C,
    or ascorbate

34
Parkinsonism
  • A slowly progressive neurological disease
    characterized by
  • a fixed inexpressive face
  • a tremor at rest, slowing of voluntary movements
  • a gait with short accelerating steps, peculiar
    posture, and muscle weakness
  • It is caused by degeneration of the basal
    ganglia, and by low production of the
    neurotransmitter dopamine
  • Most patients are over 50, but at least 10
    percent are under 40
  • Also known as paralysis agitans and shaking palsy
  • Treatment is by medication, such as levodopa and
    carbidopa (Sinemet)
  • Levodopa is converted to dopamine levodopa is
    able to pass the blood brain barrier, but
    dopamine is not able to pass the BBB
  • Carbidopa is an inhibitor of aromatic amino acid
    decarboxylase in the periphery carbidopa does
    not enter the CNS

35
Serotonin Metabolism (Fig. 19-19)
36
NOS (Fig. 19-23)
37
Recycling of Synaptic Vesicles
38
Selected Synaptic Proteins
  • Synapsin
  • A vesicle protein
  • Recruits vesicles to the synaptic region
  • Binds to the cytoskelton
  • Phosphorylation by PKA and CaM Kinase II releases
    synapsin from vesicles and allows them to move
    into the active region
  • v-SNARES for vesicle-(Soluble NSF Attachment
    protein REceptors) and NSF refers to
    N-ethylmaleimide Sensitive Factor
  • VAMP vesicle associated protein
  • Also called synaptobrevin
  • t-SNARES for target
  • Syntaxin
  • SNAP25 (synaptosomal associated protein MW 25 kDa)

39
Selected Synaptic Proteins II
  • Synaptotagmin the calcium ion sensor
  • Exocytosis is triggered by Ca2
  • Rab3A is a G protein found on vesicles and is
    required for fusion with the plasma membrane and
    exocytosis
  • Formation of a VAMP-syntaxin-SNAP25 complex
    occurs with vesicle fusion and exocytosis
  • NSF (N-ethylmaleimide sensitive factor), alpha-
    beta-, and gamma-SNAP dissociate the
    VAMP-syntaxin-SNAP25 complex (ATP dependent)
    after fusion
  • The proteins return to their initial state (in
    the vesicle or on the target membrane)
  • Action potential opens Ca2 channels in the
    synaptic region which triggers exocytosis

40
Vesicle Docking and Fusion
41
Excitation and Inhibition
  • Top frog skeletal muscle
  • Bottom frog heart
  • The Loewi experiment provided proof that
    neurotransmission is chemical in nature (as
    opposed to electrical)
  • Vagusstuff (ACh)
  • Accelerinstuff (NE)
  • Learn this experiment

42
Neurotransmitter Receptors
  • Ligand-gated receptors are fast GPCRs are slow
  • ACh and the nicotinic receptor at the
    neuromuscular junction is ligand gated and
    promotes the flux of both sodium and potassium
  • Nicotinic receptor and other ligand-gated
    receptors consists of 5 subunits
  • There are four candidate membrane-spanning
    regions for each subunit
  • An M2 alpha helix lines the ion channel
  • NT binding triggers a conformational change
    leading to channel opening
  • Glutamate
  • NMDA, AMPA, and kainate receptors are ionotropic
  • The receptor is made of five subunits
  • Segments 1,3, and 4 of each are transmembrane
    segments
  • Segment 2 courses into, but not through ,the
    membrane from the cytosolic face
  • Activation of NMDA requires depolarization and
    glutamate binding
  • There are three classes of metabolotropic
    glutamate receptors (7 TM)
  • GABA and glycine receptors are ligand-gated Cl-
    channels
  • Five subunits per receptor
  • Intricate
  • Four candidate transmembrane segments

43
Neurotransmitter Receptors II
  • ACh and muscarinic receptors in heart
  • Causes dissociation of a heterotrimeric G protein
  • G beta, gamma binds to and opens a K channel,
    and this leads to hyperpolarization (inhibition)
  • G-protein coupled catecholamine receptors lead to
    elevated cAMP

44
Ligand-gated Ion Channel Receptors
  • Note that Cl- is responsible for
    hyperpolarization
  • Note that Na is responsible for depolarization
  • These receptors are made up of 5 subunits each
    with 4 TM segments 5X4 20 TM segments

45
Neurotransmitter Receptors
46
Nicotinic Receptor and the nm Junction
  • The formation of autoantibodies against this
    receptor produces myasthenia gravis
  • Myasthenia gravis (MG) is a chronic neuromuscular
    disease characterized by varying degrees of
    weakness of the skeletal or voluntary muscles of
    the body
  • The muscle weakness increases during periods of
    activity and improves after periods of rest.
  • MG most commonly occurs in young adult women and
    older men but can occur at any age
  • Although MG may affect any voluntary muscle,
    certain muscles including those that control eye
    movements, eye lids, chewing, swallowing,
    coughing, and facial expressions are more often
    affected
  • Weakness may also occur in the muscles that
    control breathing and arm and leg movements.
  • Therapies include medications such as
    anticholinesterase agents, prednisone,
    cyclosporine, and azathioprine
  • Thymectomy
  • Plasmapheresis, a procedure in which antibodies
    are removed from blood plasma

47
Nicotinic ACh Receptor
  • Most of the protein mass is extracellular
  • There are two acetylcholine binding sites
  • There are four membrane TM segments (M1, M2, M3,
    M4) in each of the five subunits (5X420)
  • Five M2 helices form the pore
  • Aspartate and glutamate side chains at both ends
    of the pore exclude anions

48
Pore-lining M2 Helices
  • Closed state kink in the center of each M2 helix
    constricts the passageway
  • Open state kinks rotate to one side so that
    helices are farther apart
  • Only 3 of the 5 M2 helices are shown

49
Nicotinic Receptor and the nm Junction(Fig.
19-18)
50
NMDA and Non-NMDA Glu Receptors
  • NMDA is blocked by Mg2
  • Depolarization of several non-NMDA receptors
    leads to depolarization and removal of Mg2
  • Ca2 as well as Na traverse the NMDA receptor
  • This leads to an enhanced response in the
    postsynaptic cells
  • This is long-term potentiation that results from
    a burst of stimulation

51
ACh-induced Opening of K Channels in Heart
  • ACh leads to activation of the muscarinic
    receptor
  • This leads to the exchange of GTP for GDP in the
    heterotrimeric G-protein
  • The beta-gamma subunits activate a K channel
  • The outward flow of K leads to a more negative
    intracellular potential, or hyperpolarization,
    and a decreased rate of contraction

52
G-Protein Coupled Receptors (GPCRs)
53
G-Protein Linked Receptors
54
G-Protein Cycle
55
Actions of Heterotrimeric G-proteins
  • Stimulate adenylyl cyclase Gs
  • Inhibit adenylyl cyclase Gi
  • Activate phospholipase C leading to IP3 and
    diacylglycerol production Gq

56
Inactivation of NTs
  • Uptake (most prevalent form)
  • DA, NE, EPI
  • 5-HT
  • Glu
  • Gly
  • Almost all NTs except ACh and neuropeptides
  • Julius Axelrod at the NIH discovered
    norepinephrine reuptake and transformed the field
  • Hydrolysis
  • Neuropeptides
  • ACh

57
GABA Metabolism
58
An Electric Synapse
  • The plasma membranes of the pre-and post-synaptic
    cells are linked by gap junctions
  • Flow of ions through these channels allows
    electric impulses to be transmitted directly from
    one cell to the next
  • Unusual in mammals
  • Occur in fish (goldfish)

59
Transmission Across Electric and Chemical Synapses
  • Transmission across an electrical synapse is fast
    (microseconds)
  • Transmission across a chemical synapse occurs on
    the order of milliseconds
  • This was the evidence that convinced everyone
    that neurotransmission in the CNS is chemical and
    not electrical in nature

60
Sensory Transduction
  • Converts signals from the environment into
    electric signals
  • Light G-protein
  • Odor G-protein
  • Taste gated
  • Sound gated
  • Touch gated
  • Vision
  • Stimulated rhodopsin activates transducin, a
    G-protein
  • Transducin alpha-GTP activates PDE
  • PDE lowers cGMP
  • cGMP-gated Na/Ca2 are closed, membrane
    hyperpolarization occurs, and less NT is released
  • Each sensory neuron in the olfactory epithelium
    expresses a single type of odorant receptor
  • Golf are coupled to and activates adenylyl
    cyclase
  • cAMP opens gated channels causing depolarization
    of the cell membrane and generation of an action
    potential
  • The thousand or so olfactory receptors are
    intronless

61
Rod Cell
62
Hyperpolarization of the Rod-Cell Membrane
  • This system works backwards
  • Light causes hyperpolarization and decreased
    released of a NT (Glutamate)

63
Rhodopsin Metabolism
64
Actions in the Rod Cell
  • In the dark, the rod cell is hyperpolarized owing
    to the activation of a sodium channel by cGMP
  • Light activates rhodopsin, a 7 transmembrane
    segment light receptor (the first 7 TM domain
    protein to be described)
  • The heterotrimeric G-protein becomes activated
  • The active a-subunit of the G-protein binds to
    the g-subunit of phosphodiesterase (abg) to form
    a complex
  • The abcomplex of PDI is now active
  • cGMP levels fall, the sodium channel is closed,
    and the cell becomes less depolarized (i.e., more
    polarized or hyperpolarized, and less Glu is
    released)

65
Role of Transducin (Fig. 19-26)
66
Color Vision and Spectra
  • Color vision uses three opsin pigments opsins
    are proteins
  • These correspond to the three classes of cones
  • Blue
  • Green
  • Red
  • Opsins differ, but the pigment is the same
  • Red and green opsins are on chromosome X
  • Owing to recombination, X chromosomes with only a
    red or a green opsin gene is formed
  • 8 of human males leads to red-green blindness

67
Olfactory Epithelium
  • The human olfactory epithelium expresses about
    1000 different odorant receptors
  • These are G-protein linked
  • Golf
  • Activate adenylyl cyclase
  • cAMP-gated channel induces depolarization
  • (b,c) Odorant cells expressing the same receptor
    project to the same point in the olfactory bulb

68
Channel Summary
  • Resting, always open
  • Voltage gated K and cyclic nucleotide gated
  • Four proteins with 6 TM segments 24 TM segments
  • Voltage-gated Na and Ca channels
  • 24 TM segments
  • Ligand gated (ACh, Glu) Na channels
  • Five subunits with four TM segments 20 TM
    segments total
  • Ligand gated (GABA, Gly)
  • Five subunits with four TM segments 20 TM
    segments total
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