Transmitter-Gated Channels The Basic Structure of Transmitter-Gated ...
Transmitter-Gated Channels
The Basic Structure of Transmitter-Gated Channels Four different types of polypeptides are used as subunits for the nicotinic receptor, and they are designated as: β, α, δ, and γ. A complete mature channel is made from two α subunits, and one each of β, δ and γ. There is one ACh binding site on each of the α subunits; the simultaneous binding of ACh to both sites is required for the channel to open The structure of glutamate receptors resembles that of potassium channels, and this has inspired the surprising hypothesis that glutamate receptors and potassium channels evolved from a common ancestral ion channel Amino Acid-Gated Channels Amino acid-gated channels mediate most of the fast synaptic transmission in the CNS Several properties of these channels distinguish them from one another: o Pharmacology of their binding sites describes which transmitters affect them and how drugs interact with them o Kinetics of the transmitter binding process and channel gating determine the duration of their effect o Selectivity of the ion channels determines whether they produce excitation or inhibition and whether Ca2+ enters the cell in significant amounts o Conductance of open channels helps determine the magnitude of their effects Glutamate-Gated Channels: 3 Glutamate Receptor Subtypes: AMPA, NMDA, and Kainate AMPA-gated and NMDA-gated channels mediate the bulk of fast excitatory synaptic transmission in the brain AMPA-gated channels are permeable to both sodium and potassium but not calcium AMPA channels can be activated by a rapid increase in sodium ions into the cell, thus depolarizing the cells AMPA receptors coexist with NMDA receptors at many synapses in the brain, so most glutamate-mediated EPSPs have components contributed by both NMDA-gated channels also cause excitation of a cell by admitting sodium, but they differ from AMPA receptors in two very important ways: o NMDA-gated channels are permeable to calcium o Inward ionic current through NMDA-gated channels is voltage dependent If excessive amounts of calcium are released, it can trigger the death of a cell Activation of NMDA receptors can cause widespread and lasting changes in the postsynaptic neuron Inward ionic current through the NMDA channel is voltage dependent
G-Protein-Coupled Receptors and Effectors Transmission at the G-protein-coupled receptors involves 3 steps: o Binding of the neurotransmitter to the receptor protein o Activation of G-proteins o Activation of effector systems
The Basic Structure of G-Protein-Coupled Receptors Most G-protein-coupled receptors are simple variations on a common plan, consisting of a single polypeptide containing seven membrane-spanning alpha helices Two of the extracellular loops of the polypeptide form the transmitter binding sites Structural variations in this region determine which neurotransmitters, agonists, and antagonists bind to the receptor Two of the intracellular loops can bind to and activate G-proteins and, consequently, which effector systems are activated in response to transmitter binding
The Ubiquitous G-Proteins: G-Protein = Guanosine Triphosphate (GTP) binding protein Basic Mode of operation of a G-Protein [Fig. 6.24, Pg. 159] o In the normal inactive state, a GDP from the cytosol binds to the alpha subunit of the G-Protein.
o o o o
This GDP binding causes the G-Protein to bind to a coupled receptor which in turn causes the G-Protein to release the GDP and exchange it for a GTP from the cytosol. The activated G-Protein splits into two pieces with the beta & the gamma on one side and alpha with the GTP on the other side. Both become available to activate effector proteins. The alpha subunit removes the phosphate from its GTP making it a GDP again; this causes it to terminate its own activity. Both sides of the G-Protein come back together, allowing the cycle to be repeated again.
G-Protein-Coupled Effector Systems: Activated G-proteins exert their effects by binding to either of two types of effector proteins: o G-protein-gated ion channels and G-protein-activated potassium o If there are no intermediaries, the first route is sometimes called the shortcut pathway The Shortcut Pathway: Shortcut pathways are the fastest of the G-protein-coupled systems, having responses beginning within 30-100 msec of neurotransmitter binding This is faster than the second messenger cascades This is also very localized compared with other effector systems As the G-protein diffuses within the membrane, it apparently cannot move very far, so only channels nearby can be affected
Second Messenger Cascades G-proteins can also exert their effects by directly activating certain enzymes Second Messenger Cascade- A multistep process that couples activation of a neurotransmitter receptor to activation of intracellular enzymes.
Divergence & Convergence The ability of one transmitter to activate more than one subtype of receptor, and cause more than one type of postsynaptic response is called divergence Every known neurotransmitter can activate multiple receptor subtypes Multiple transmitters each activating their own receptor type can converge to affect the same effector systems, called convergence Convergence in a single cell can occur at the level of the G-protein, second messenger cascade, or the type of ion channel Neurons integrate divergent and convergent signalling systems
The Basic Structure of Transmitter-Gated Channels Four different types of polypeptides are used as subunits for the nicotinic receptor, and they are designated as: β, α, δ, and γ. A complete mature channel is made from two α subunits, and one each of β, δ and γ. There is one ACh binding site on each of the α subunits; the simultaneous binding of ACh to both sites is required for the channel to open The structure of glutamate receptors resembles that of potassium channels, and this has inspired the surprising hypothesis that glutamate receptors and potassium channels evolved from a common ancestral ion channel Amino Acid-Gated Channels Amino acid-gated channels mediate most of the fast synaptic transmission in the CNS Several properties of these channels distinguish them from one another: o Pharmacology of their binding sites describes which transmitters affect them and how drugs interact with them o Kinetics of the transmitter binding process and channel gating determine the duration of their effect o Selectivity of the ion channels determines whether they produce excitation or inhibition and whether Ca2+ enters the cell in significant amounts o Conductance of open channels helps determine the magnitude of their effects Glutamate-Gated Channels: 3 Glutamate Receptor Subtypes: AMPA, NMDA, and Kainate AMPA-gated and NMDA-gated channels mediate the bulk of fast excitatory synaptic transmission in the brain AMPA-gated channels are permeable to both sodium and potassium but not calcium AMPA channels can be activated by a rapid increase in sodium ions into the cell, thus depolarizing the cells AMPA receptors coexist with NMDA receptors at many synapses in the brain, so most glutamate-mediated EPSPs have components contributed by both NMDA-gated channels also cause excitation of a cell by admitting sodium, but they differ from AMPA receptors in two very important ways: o NMDA-gated channels are permeable to calcium o Inward ionic current through NMDA-gated channels is voltage dependent If excessive amounts of calcium are released, it can trigger the death of a cell Activation of NMDA receptors can cause widespread and lasting changes in the postsynaptic neuron Inward ionic current through the NMDA channel is voltage dependent
G-Protein-Coupled Receptors and Effectors Transmission at the G-protein-coupled receptors involves 3 steps: o Binding of the neurotransmitter to the receptor protein o Activation of G-proteins o Activation of effector systems
The Basic Structure of G-Protein-Coupled Receptors Most G-protein-coupled receptors are simple variations on a common plan, consisting of a single polypeptide containing seven membrane-spanning alpha helices Two of the extracellular loops of the polypeptide form the transmitter binding sites Structural variations in this region determine which neurotransmitters, agonists, and antagonists bind to the receptor Two of the intracellular loops can bind to and activate G-proteins and, consequently, which effector systems are activated in response to transmitter binding
The Ubiquitous G-Proteins: G-Protein = Guanosine Triphosphate (GTP) binding protein Basic Mode of operation of a G-Protein [Fig. 6.24, Pg. 159] o In the normal inactive state, a GDP from the cytosol binds to the alpha subunit of the G-Protein.
o o o o
This GDP binding causes the G-Protein to bind to a coupled receptor which in turn causes the G-Protein to release the GDP and exchange it for a GTP from the cytosol. The activated G-Protein splits into two pieces with the beta & the gamma on one side and alpha with the GTP on the other side. Both become available to activate effector proteins. The alpha subunit removes the phosphate from its GTP making it a GDP again; this causes it to terminate its own activity. Both sides of the G-Protein come back together, allowing the cycle to be repeated again.
G-Protein-Coupled Effector Systems: Activated G-proteins exert their effects by binding to either of two types of effector proteins: o G-protein-gated ion channels and G-protein-activated potassium o If there are no intermediaries, the first route is sometimes called the shortcut pathway The Shortcut Pathway: Shortcut pathways are the fastest of the G-protein-coupled systems, having responses beginning within 30-100 msec of neurotransmitter binding This is faster than the second messenger cascades This is also very localized compared with other effector systems As the G-protein diffuses within the membrane, it apparently cannot move very far, so only channels nearby can be affected
Second Messenger Cascades G-proteins can also exert their effects by directly activating certain enzymes Second Messenger Cascade- A multistep process that couples activation of a neurotransmitter receptor to activation of intracellular enzymes.
Divergence & Convergence The ability of one transmitter to activate more than one subtype of receptor, and cause more than one type of postsynaptic response is called divergence Every known neurotransmitter can activate multiple receptor subtypes Multiple transmitters each activating their own receptor type can converge to affect the same effector systems, called convergence Convergence in a single cell can occur at the level of the G-protein, second messenger cascade, or the type of ion channel Neurons integrate divergent and convergent signalling systems
