Neuroscience Metabotropic Receptors Quiz
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Questions and Answers

What types of human samples are essential for mining targets relevant to a disease?

Nervous tissue, blood, and cerebral spinal fluid are essential human samples.

How can one confirm the expression of a target in disease-related research?

By confirming GABA expression in models such as 'depressed' mice at relevant diseased sites.

What are two genetic models used to modify target gene expression?

'Knock-outs' to delete gene of interest and 'knock-ins' to augment gene activity or quantity.

What is the purpose of High Throughput Screening (HTS) in drug discovery?

<p>HTS develops assays to screen large compound libraries for activation or inhibition of drug targets.</p> Signup and view all the answers

What challenges might arise when using pharmacological tools for target validation?

<p>Pharmacological tools may not be selective for the target and could have off-target effects.</p> Signup and view all the answers

What defines a metabotropic receptor compared to an ionotropic receptor?

<p>A metabotropic receptor does not have a channel and acts through G-proteins to trigger second messenger systems, while an ionotropic receptor directly opens ion channels.</p> Signup and view all the answers

How do second messengers contribute to cellular signaling in neurons?

<p>Second messengers, such as cAMP and cGMP, modify ion channel conformation and other cellular functions, facilitating slower and longer-lasting effects compared to direct ion flux.</p> Signup and view all the answers

What is the role of autoreceptors in neurotransmitter regulation?

<p>Autoreceptors are located on presynaptic terminals and typically inhibit neurotransmitter production to provide feedback to the originating neuron.</p> Signup and view all the answers

What ion's influx primarily triggers an Inhibitory Postsynaptic Potential (IPSP)?

<p>Cl- flows in.</p> Signup and view all the answers

Describe the processes that terminate neurotransmitter communication.

<p>Neurotransmitter communication is terminated by reuptake, where transporters recycle neurotransmitters, and deactivation, where enzymes break them down.</p> Signup and view all the answers

What is the significance of ion flow in determining a neuron's excitatory or inhibitory state?

<p>The net influx or outflux of ions, such as Na+ for excitation and Cl- for inhibition, determines whether the postsynaptic neuron is depolarized or hyperpolarized.</p> Signup and view all the answers

Identify the number of ion channels that have been identified thus far.

<p>More than 200 ion channels.</p> Signup and view all the answers

What significant effect can a mutation in ion channels lead to, as seen in 'channelopathies'?

<p>It can trigger or prevent a disease or condition.</p> Signup and view all the answers

What is the axon hillock's role in action potential generation?

<p>The axon hillock integrates EPSPs and IPSPs, and when the membrane potential reaches -55 mV, it triggers an action potential.</p> Signup and view all the answers

How does the Nav1.7 channel affect a person's sensation of pain?

<p>People lacking Nav1.7 channels do not feel pain.</p> Signup and view all the answers

Explain how drugs can influence neurotransmitter activity in the context of receptor action.

<p>Drugs can act on binding sites of receptors, interfere with second messenger systems, or target ion channels to modulate neurotransmitter effects.</p> Signup and view all the answers

Distinguish between EPSP and IPSP effects on the postsynaptic neuron.

<p>EPSP results in depolarization of the postsynaptic neuron, making it more likely to fire, while IPSP leads to hyperpolarization, reducing the likelihood of firing.</p> Signup and view all the answers

Name one type of gated channel that is activated by changes in the membrane potential.

<p>Voltage Dependent (Gated) Channels.</p> Signup and view all the answers

What is the function of ligand-gated receptors in the context of ion channels?

<p>They open in response to the binding of a molecule to the receptor.</p> Signup and view all the answers

List the three states of a voltage-gated channel.

<p>Closed, activated, and inactivated.</p> Signup and view all the answers

Which receptor type includes P2X receptors and ionic glutamate receptors?

<p>Ligand Gated Receptors (Ionotropic Receptors).</p> Signup and view all the answers

What are two examples of physiological responses influenced by animal toxins related to ion channels?

<p>Disturbances in nerve signaling and paralysis.</p> Signup and view all the answers

Which channel is implicated in both pain sensation and its absence?

<p>Nav1.7 channel.</p> Signup and view all the answers

What is the primary function of KV channels in neurons?

<p>KV channels allow the flow of K+ out of the neuron, facilitating repolarization.</p> Signup and view all the answers

How many main subtypes of KV channels are there?

<p>There are 12 main subtypes of KV channels.</p> Signup and view all the answers

What triggers the activation of KV channels?

<p>KV channels are mainly activated by high positive voltages.</p> Signup and view all the answers

What distinguishes ligand-gated channels from voltage-dependent channels?

<p>Ligand-gated channels open and close in response to the presence of specific ligands.</p> Signup and view all the answers

What ions enter the neuron when P2X receptors are activated?

<p>P2X receptors allow the inflow of Na+ and Ca2+ ions.</p> Signup and view all the answers

What is the role of the three subtypes of ionotropic glutamate receptors?

<p>The three subtypes (NMDA, AMPA, and others) allow in-flow of Na+, facilitating depolarization.</p> Signup and view all the answers

How many subtypes of P2X receptors are identified?

<p>There are 7 subtypes of P2X receptors, from P2X1 to P2X7.</p> Signup and view all the answers

What type of ions can flow through iGluRs upon activation?

<p>iGluRs allow the flow of Na+ and also K+ ions upon activation.</p> Signup and view all the answers

What is the role of ATP in the function of P2X receptors?

<p>ATP acts as a ligand that activates P2X receptors, leading to ion flow.</p> Signup and view all the answers

What is a significant difference between ionotropic and metabotropic glutamate receptors?

<p>Ionotropic glutamate receptors mediate rapid synaptic transmission, while metabotropic receptors activate second messengers.</p> Signup and view all the answers

What enzyme is responsible for breaking down glutamate into glutamine?

<p>Glutamine synthase</p> Signup and view all the answers

Which group of metabotropic receptors is located postsynaptically and involved in excitatory transmission?

<p>Group I (mGluR1, mGluR5)</p> Signup and view all the answers

What is the main inhibitory neurotransmitter found throughout the nervous system?

<p>GABA (γ-aminobutyric acid)</p> Signup and view all the answers

Identify the enzyme that degrades GABA.

<p>GABA aminotransferase (GABA-AT)</p> Signup and view all the answers

What neurotransmitter is synthesized from glutamate via glutamate decarboxylase?

<p>GABA</p> Signup and view all the answers

What is the primary function of acetylcholinesterase in neurotransmitter regulation?

<p>To degrade acetylcholine (ACh)</p> Signup and view all the answers

Which receptors are mainly activated by muscarine?

<p>Muscarinic ACh receptors (mACh)</p> Signup and view all the answers

Name two major pathways of acetylcholine projections.

<p>Basal forebrain and pontine tegmental areas</p> Signup and view all the answers

Which type of receptors do both ligand-gated and metabotropic forms of neurotransmitters belong to?

<p>ACh, glutamate, and GABA receptors</p> Signup and view all the answers

What well-known lifestyle drug reduces acetylcholine release?

<p>Caffeine</p> Signup and view all the answers

What are two functions of peptides as neurotransmitters?

<p>Peptides act as neuromodulators and neurotransmitters, capable of diffusing to other neurons and cells.</p> Signup and view all the answers

How are lipids typically released in the nervous system?

<p>Lipids are released directly through the lipid membrane of the post-synaptic neuron.</p> Signup and view all the answers

List one example of a neurotransmitter that is a peptide and one that is a lipid.

<p>An example of a peptide neurotransmitter is substance P, and a lipid neurotransmitter is anandamide.</p> Signup and view all the answers

What role does target identification play in modern drug discovery?

<p>Target identification involves finding mechanisms linked to the disease's pathophysiology.</p> Signup and view all the answers

What might happen if there is dysfunction among neurotransmitters in the CNS?

<p>Dysfunction of neurotransmitters is linked to the majority of neurological disorders.</p> Signup and view all the answers

How many subtypes of Nav channels are there?

<p>There are 9 subtypes of Nav channels, labeled Nav1.1 to Nav1.9.</p> Signup and view all the answers

What role do CaV channels play in neurons?

<p>CaV channels allow the flow of Ca2+ into the neuron and are crucial for neurotransmitter release.</p> Signup and view all the answers

What differentiates TTXs from TTXr Nav channels?

<p>TTXs are sensitive to tetrodotoxin, while TTXr channels are resistant to it.</p> Signup and view all the answers

What triggers the activation of CaV channels?

<p>CaV channels are activated during depolarization, typically in the high to moderate voltage range.</p> Signup and view all the answers

How do low voltage activated (LVA) CaV channels differ from others?

<p>LVA CaV channels are activated close to the resting potential compared to others that require higher voltages.</p> Signup and view all the answers

Identify the types of NaV channel subtypes resistant and sensitive to TTX.

<p>Nav1.5, Nav1.8, and Nav1.9 are TTXr, while all other Nav channels are TTXs.</p> Signup and view all the answers

What are the voltage activation characteristics of Cav3 channels?

<p>Cav3 channels are low voltage activated, responding near the resting membrane potential.</p> Signup and view all the answers

What is the significance of the number of human Kv channel subtypes?

<p>The human Kv channels have several subtypes crucial for diverse physiological processes.</p> Signup and view all the answers

How do high voltage activated (HVA) CaV channels function during an action potential?

<p>HVA CaV channels open during the depolarization phase of an action potential.</p> Signup and view all the answers

What is triggered by the influx of Cl- ions?

<p>An Inhibitory Postsynaptic Potential (IPSP) is triggered.</p> Signup and view all the answers

What role do Nav1.7 channels play in pain sensation?

<p>Nav1.7 channels are essential for the sensation of pain.</p> Signup and view all the answers

What distinguishes voltage-gated channels from ligand-gated channels?

<p>Voltage-gated channels respond to changes in membrane potential, while ligand-gated channels open upon binding a specific molecule.</p> Signup and view all the answers

Which types of receptors include serotonin receptor 3 and GABAA?

<p>These are examples of ligand-gated receptors, also known as ionotropic receptors.</p> Signup and view all the answers

What is a channelopathy?

<p>A channelopathy is a disease or condition caused by a malfunction in ion channel function due to mutations.</p> Signup and view all the answers

How do voltage-gated channels change states upon activation?

<p>Voltage-gated channels transition from a closed state to an activated state and then to an inactivated state.</p> Signup and view all the answers

What is the primary function of GABA in the nervous system?

<p>GABA acts as the main inhibitory neurotransmitter, reducing neuronal excitability.</p> Signup and view all the answers

What effect do animal toxins have on ion channels?

<p>Animal toxins often disrupt the normal function of ion channels, impacting nerve signal transmission.</p> Signup and view all the answers

What is the primary role of Kv channels in neurons?

<p>The primary role of Kv channels in neurons is to allow the flow of K+ out of the neuron, facilitating repolarization.</p> Signup and view all the answers

How does activation of P2X receptors affect ion flow in neurons?

<p>Activation of P2X receptors allows the in-flow of Na+ and Ca2+, contributing to depolarization, and also permits K+ flow.</p> Signup and view all the answers

What role does glycine play in the activation of NMDA receptors?

<p>Glycine is necessary for the activation of NMDA receptors along with glutamate.</p> Signup and view all the answers

What distinguishes the 7 subtypes of P2X receptors?

<p>The 7 subtypes of P2X receptors, from P2X1 to P2X7, are distinguished by their specific activation by ATP and analogs.</p> Signup and view all the answers

What ions are primarily allowed to flow through ionotropic glutamate receptors (iGluRs) upon activation?

<p>Upon activation, iGluRs primarily allow the flow of Na+ into the neuron and K+ out.</p> Signup and view all the answers

Which ions are allowed to flow through the 5-HT3 receptor upon activation?

<p>The 5-HT3 receptor allows in-flow of Na+ and Ca2+, and also permits flow of K+.</p> Signup and view all the answers

Identify the specific channel activated by capsaicin among the TRP channels.

<p>Capsaicin activates the TRPV1 channel.</p> Signup and view all the answers

What are the three subtypes of ionotropic glutamate receptors and their distinct ligands?

<p>The three subtypes of ionotropic glutamate receptors are NMDA, AMPA, and kainate, activated by their respective ligands.</p> Signup and view all the answers

What is the significance of having many subtypes of KV channels?

<p>The significance of having many subtypes of KV channels lies in their diverse functions and roles in different types of neurons.</p> Signup and view all the answers

What effect does activation of GABAA receptors have on neuronal membrane potential?

<p>Activation of GABAA receptors allows in-flow of Cl-, leading to hyperpolarization.</p> Signup and view all the answers

How many ACh molecules are needed for the activation of nicotinic acetylcholine receptors?

<p>Two ACh molecules are required for the activation of nicotinic acetylcholine receptors.</p> Signup and view all the answers

What effect does the presence of ligand have on ligand-gated channels?

<p>The presence of a ligand causes ligand-gated channels to open or close, thereby regulating ion flow.</p> Signup and view all the answers

What are the main pathways in which dopamine is involved?

<p>Dopamine is involved in motor function, reward, cognition, and learning.</p> Signup and view all the answers

In terms of Kv channels, what voltage primarily triggers their activation?

<p>Kv channels are mainly activated by high (positive) voltages.</p> Signup and view all the answers

What distinguishes the D1-like receptors from D2-like receptors in the dopamine system?

<p>D1 and D5 receptors are excitatory (D1-like), while D2, D3, and D4 receptors are inhibitory (D2-like).</p> Signup and view all the answers

How many main subtypes of P2X receptors are identified?

<p>There are 7 main subtypes of P2X receptors identified, ranging from P2X1 to P2X7.</p> Signup and view all the answers

What physiological ion flow pattern is associated with activated iGluR receptors?

<p>Activated iGluR receptors primarily result in Na+ influx and K+ efflux, promoting depolarization.</p> Signup and view all the answers

What types of ions can flow through TRP cation channels when activated?

<p>TRP cation channels allow in-flow of Na+ and Ca2+, and also permit flow of K+.</p> Signup and view all the answers

What is the primary function of neurotransmitters in the nervous system?

<p>Neurotransmitters facilitate communication between neurons across synapses.</p> Signup and view all the answers

Which type of receptor predominantly causes hyperpolarization when activated?

<p>The GABAA receptor causes hyperpolarization upon activation.</p> Signup and view all the answers

Which of the following groups includes neurotransmitters that act as neuromodulators?

<p>Peptides and Lipids</p> Signup and view all the answers

What is a characteristic feature of lipid neurotransmitters in the nervous system?

<p>Utilized in retrograde transmission</p> Signup and view all the answers

What is the role of enzymes in the degradation of peptides as neurotransmitters?

<p>They degrade peptides but are not involved in reuptake.</p> Signup and view all the answers

Which neurotransmitter can be categorized as both a peptide and a lipid?

<p>Substance P</p> Signup and view all the answers

How are neurotransmitters like neurotransmitter Y typically involved in neurological disorders?

<p>Dysfunction of these neurotransmitters is often linked to neurological disorders.</p> Signup and view all the answers

What is the function of NMDA receptors in neuronal signaling?

<p>They require both glutamate and glycine for activation.</p> Signup and view all the answers

Which of the following is true about 5-HT3 serotonin receptors?

<p>They are activated by serotonin and allow Na+ and Ca2+ influx.</p> Signup and view all the answers

What happens when GABAA receptors are activated?

<p>They allow Cl- influx, leading to hyperpolarization.</p> Signup and view all the answers

Which cation channels are activated by heat and chemical irritants?

<p>TRPV1 channels.</p> Signup and view all the answers

How many receptor subtypes are there in the Nicotinic Acetylcholine Receptor family?

<p>11 subtypes.</p> Signup and view all the answers

What role do ion channels play in neuronal signaling?

<p>They can be both voltage-dependent and ligand-dependent.</p> Signup and view all the answers

What neurotransmitter is synthesized from L-Tryptophan?

<p>Serotonin (5-HT).</p> Signup and view all the answers

Which neurotransmitter is associated with inhibitory signaling in the CNS?

<p>GABA.</p> Signup and view all the answers

Which cation channels allow for the flow of Na+ and Ca2+ upon activation?

<p>Both B and C.</p> Signup and view all the answers

What is the primary function of nicotinic acetylcholine receptors (nAChR)?

<p>To enable in-flow of Na+ and Ca2+, leading to depolarization.</p> Signup and view all the answers

What is the primary function of metabotropic receptors in neurotransmitter signaling?

<p>Trigger a second messenger system</p> Signup and view all the answers

Which of the following describes a key difference between excitatory and inhibitory postsynaptic potentials?

<p>Inhibitory potentials result in hyperpolarization</p> Signup and view all the answers

What mechanism is responsible for terminating neurotransmitter communication?

<p>Reuptake and enzymatic deactivation</p> Signup and view all the answers

What effect does an influx of positive ions such as Na+ have on a neuron?

<p>It leads to an action potential if strong enough</p> Signup and view all the answers

Which of the following describes autoreceptors in the context of neurotransmitter regulation?

<p>Inhibit production of neurotransmitters</p> Signup and view all the answers

What is a characteristic feature of metabotropic receptors compared to ionotropic receptors?

<p>They utilize G-proteins to effect changes</p> Signup and view all the answers

What substance is commonly known as a second messenger in cellular signaling?

<p>Cyclic adenosine monophosphate (cAMP)</p> Signup and view all the answers

What is the significance of the axon hillock in neuronal firing?

<p>It integrates Ion channel activities and generates action potentials</p> Signup and view all the answers

Which pathway connects the substantia nigra to the striatum?

<p>Nigrostriatal pathway</p> Signup and view all the answers

What neurotransmitter is primarily involved in the stress response and arousal?

<p>Noradrenaline</p> Signup and view all the answers

Which enzyme is responsible for the degradation of dopamine in presynaptic terminals?

<p>Monoamine oxidase (MAO-A)</p> Signup and view all the answers

What type of receptors do noradrenaline and epinephrine primarily bind to?

<p>Metabotropic receptors</p> Signup and view all the answers

Which type of receptor is primarily inhibitory among the noradrenaline receptors?

<p>α2 receptors</p> Signup and view all the answers

Which neurotransmitter is associated with mood regulation, aggression, and sleep?

<p>Serotonin</p> Signup and view all the answers

Where do most 5-HT neurons reside in the brain?

<p>Dorsal raphe</p> Signup and view all the answers

Which neurotransmitter does NOT have a specific reuptake transporter?

<p>Histamine</p> Signup and view all the answers

Which pathway originates from the ventral tegmental area and projects to the limbic area?

<p>Mesolimbic pathway</p> Signup and view all the answers

What is the primary function of monoamine oxidase (MAO) in neurotransmitter regulation?

<p>Degrade neurotransmitters in presynaptic terminals</p> Signup and view all the answers

Which enzyme degrades dopamine in both the postsynaptic neuron and in astrocytes?

<p>Catechol-O-methyltransferase (COMT)</p> Signup and view all the answers

What type of receptors are mGluR1 and mGluR5 classified as?

<p>Excitatory transmission receptors</p> Signup and view all the answers

Which group of metabotropic glutamate receptors functions primarily as presynaptic autoreceptors?

<p>Group II</p> Signup and view all the answers

What is the main role of GABA transporters (GAT-1, GAT-2, GAT-3)?

<p>To transport GABA back into the presynaptic neuron</p> Signup and view all the answers

Which acetylcholine receptor subtypes are known to have inhibitory effects?

<p>M2, M4</p> Signup and view all the answers

What enzyme is primarily responsible for degrading acetylcholine?

<p>Acetylcholinesterase (AChE)</p> Signup and view all the answers

What primary neurotransmitter is synthesized from glutamate through glutamate decarboxylase?

<p>GABA</p> Signup and view all the answers

Contrary to most neurotransmitter systems, which type of neurotransmitter does not undergo reuptake after being released?

<p>Acetylcholine</p> Signup and view all the answers

What is the primary function of the metabotropic GABA receptor GABA_B?

<p>To mediate inhibitory signaling in the nervous system</p> Signup and view all the answers

What group of metabotropic glutamate receptors includes heteroreceptors that are responsive to glial cells?

<p>Group III</p> Signup and view all the answers

Study Notes

Metabotropic Receptors

  • Sometimes called G-coupled receptors.
  • Only have a binding site, no channel.
  • Triggers a second-messenger system through G-proteins.
  • Can indirectly open ion channels by intracellular processes.
  • Slower due to indirect action on ion channels, changing ion channel function is key to modulating neuron signaling.
  • Drugs can act at the binding site, second-messenger system, or on the ion channel.

Second Messenger System

  • Neurotransmitters bind to receptors and activate G-proteins, triggering production of second messengers.
  • Second messengers can change the conformation of nearby ion channels.
  • Second messengers also affect other cell functions.
  • Types of second messenger systems include: cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP).

Neurotransmitter Actions

  • Neurotransmitters can bind to post-synaptic receptors.
  • Neurotransmitters can also bind to pre-synaptic receptors, providing feedback to the originating neuron (pre-synaptic).

Autoreceptors and Heteroreceptors

  • Receptors on terminals of presynaptic neurons.
  • Typically inhibit production of self (auto) or other (hetero) neurotransmitters.
  • Receptors provide feedback inhibition.
  • Are also a site of drug action to slow or increase production of neurotransmitters.

Regulating Neurotransmitter Communication

  • Neurotransmitter communication is brief and is stopped by reuptake or deactivation.
  • Reuptake: Transporters return neurotransmitters to the neuron (then recycled or degraded).
  • Deactivation: Enzymes break down neurotransmitters in the synaptic cleft, astrocytes, or within the neuron.
  • Prevents build-up of neurotransmitters (reinstates dynamics of communication).
  • Allows neurons to react to new signaling/information (build-up would "clog" the cleft).
  • Drugs are designed to interrupt or aid these processes.

Ion Channels on the Post-Synaptic Neuron

  • Transmitters released from pre-synaptic neurons determine the excitation or inhibition of the post-synaptic neuron.
  • The "net" influx/outflux of ions through ion channels determines the outcome (excitation or inhibition): Na+, Ca2+, Cl-, K+.
  • Ion flow "in-out" follows the same principles as action potentials: diffusion, electrostatic.
  • Triggered directly by ionotropic receptors and indirectly by metabotropic receptors.

Excitatory Postsynaptic Potential (EPSP)

  • Positive ions flow in (e.g., Na+, Ca2+)
  • Makes the inside less negative (depolarized).

Inhibitory Postsynaptic Potential (IPSP)

  • Negative ions flow in (e.g., Cl-) or positive ions flow out (e.g., K+).
  • Makes the inside more negative (hyperpolarized).

The Net EPSPs and IPSPs

  • Contribute to the firing of the neuron: excitation or inhibition.
  • If overwhelming EPSPs, the signal hits the axon hillock (-55mV) to trigger an action potential.
  • If more IPSPs, the neuron remains hyperpolarized, preventing an action potential.

Ion Channels

  • Found throughout the human body and cells.
  • All neurons have ion channels.
  • More than 200 ion channels identified.
  • Animal toxins work on ion channels.
  • More than 60 channelopathies (mutation in a channel triggers or prevents a disease/condition).

Ion Channels as Drug Targets

  • Voltage dependent (gated) channels: Channel opening depends on the membrane potential.
    • Sodium channels (Nav)
    • Calcium channels (Cav)
    • Potassium channels (Kv)
  • Ligand Gated Receptors (Ionotropic Receptors): Channel opening depends on binding of a molecule to the receptor:
    • P2X receptors
    • Ionic glutamate receptors (iGluR)
    • Serotonin receptor 3 (5-HT3)
    • Transient Receptor Potential (TRP) cation channels
    • -aminobutyric acid receptor A (GABAA)
    • Nicotinic acetylcholine receptors (nAChR)

Voltage Gated Channels

  • Three states:
    • Closed
    • Activated
    • Inactivated

Kv Channels

  • Allow flow of K+ out of the neuron (repolarization).
  • Mainly activated by high (positive) voltages (with some exceptions).
  • Kv1 through Kv12 with many "sub-subtypes".
  • Largest number of subtypes are 8 (Kv1.1 - Kv1.8).

Ligand Gated Channels

  • Opening and closing depends on the presence of a ligand.

P2X Receptors

  • Activated by ATP (adenosine 5’-triphosphate) and analogs.
  • Flow of Na+ and Ca2+ (depolarization) when activated.
  • Also allows flow of K+.
  • 7 Subtypes: P2X1-P2X.7.

Ionotropic Glutamate Receptors (iGluR)

  • When activated, allows in-flow of Na+ (depolarization).
  • Also allows the flow of K+.
  • Metabotropic glutamate receptors also exist.
  • Three distinct subtypes, named after the ligand that actives them.
      1. NMDA (N-methyl-D-aspartate)
      1. AMPA (α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid)

Amino Acid Neurotransmitters: Glutamate

  • Both ligand-gated (ionotropic) and G-coupled (metabotropic) receptors.
  • Metabotropic receptors: mGluR1-mGluR8.
  • Group I (mGluR1, mGluR5) located post-synaptically: excitatory transmission
  • Group II (mGluR2, mGluR3) located both post-synaptically and presynaptically: inhibitory transmission, autoreceptors.
  • Group III (mGluR4, mGluR6, mGluR7, mGluR8): heterreceptors
  • Found throughout the nervous system.
  • Glutamate Destruction/Reuptake:
    • Glutamine synthase (enzyme) breaks down glutamate to glutamine.
    • Removed by excitatory amino acid transporters (EAAT1-5).

Amino Acid Neurotransmitters: GABA

  • γ-aminobutyric acid (GABA)
  • Both ligand-gated (ionotropic) and G-coupled (metabotropic) receptors.
  • Metabotropic receptor: GabaB.
  • Synthesized from glutamate (via glutamate decarboxylase (GAD)).
  • Found post- and pre-synaptically.
  • Found throughout the nervous system.
  • Main inhibitory transmitter.
  • GABA destruction/reuptake:
    • Removed by GABA transporters: GAT-1, GAT-2, GAT-3.
    • Degraded by GABA Aminotransferase (GABA-AT).

Neurotransmitters: Acetylcholine

  • Acetylcholine (ACh)
  • Both ligand-gated (ionotropic) and G-coupled (metabotropic) receptors.
  • Metabotropic receptors: muscarinic mACh (most common ACh receptor)
    • Activated by muscarine
  • Both ionotropic and metabotropic receptors are activated by ACh.

Neurotransmitters: Acetylcholine (ACh)

  • Two major pathways
      1. Basal forebrain projects: cortical, thalamic, and limbic (amygdala and hippocampus) sites (sleep, arousal, attention, memory, cognition).
      1. Pontine tegmental areas project: subcortical sites and spinal cord (arousal, reward, attention, pain, motor).
  • Two other regions with localized ACh (motor, reward, cognition)
    • Striatum
    • Cerebellum

Neurotransmitters: Acetylcholine (ACh)

  • Five receptor subtypes (M1-M5)
  • M1, M3, M5 are excitatory.
  • M2 (mainly heart), M4 are inhibitory.
  • ACh destruction/reuptake:
    • Acetylcholinesterase (AChE)
    • No reuptake

Identifying Drug Targets

  • Access to human samples to mine for disease-related targets:
    • Nervous tissue: brain, spinal cord, peripheral nerves.
    • Blood
    • Cerebral spinal fluid

Target Validation

  • Is the target really linked to the disease in question?
  • Develop in vitro, ex vivo, in vivo models to investigate the relationship between the target and disease.
  • Confirm expression of the target in relevant diseased sites: GABA expression in depressed mice.
  • Non-desired tissue: Can the target be found in other tissues? (Can be an issue).
  • Use pharmacological tools to test hypotheses, if available.
    • Dirty Drug: May not be selective for the target (have activity at other targets)
  • Genetic models: What happens when the gene expression for that target is changed?
    • Knock-outs: gene of interest is deleted from the genome.
    • Knock-ins: Augment activity/quantity of gene of interest.

Identifying Early Chemical Matter: "Hit"

  • Screen your compound library: Pharmaceutical companies have millions of compounds in their libraries.
  • High-throughput screening (HTS): Assay addresses a functional component of the drug/target.
  • Robots: HTS uses a variety of techniques to allow high-throughput screening.
  • Cell-based Assays: Amenable to large "plate" platforms (96…6144 wells).
  • Activate/Block: Do any compounds in the library activate or block the functional assay results?

Understanding Drug Discovery

  • Drug discovery involves identifying a disease and its underlying mechanisms or targets.
  • Targets are specific mechanisms involved in the disease's development and progression.
  • Targets could include receptors, neurotransmitters, reuptake systems, cytokines, or ion channels.

Neurotransmitters

  • Chemical messengers packaged in synaptic vesicles and released by neurons to communicate across a synapse
  • Approximately 100 neurotransmitters are known
  • The 10 most prevalent neurotransmitters are the most studied

Neurotransmitters: Monoamines

  • Dopamine (DA)
    • G-coupled (metabotropic) receptors
    • Five receptor subtypes (D1-D5)
      • D1 and D5 are excitatory
      • D2, D3, and D4 are inhibitory
    • Involved in motor function, reward, cognition, learning, motivation, pleasure, cognition, fear, learning, emotion, executive functioning
    • Three main pathways:
      • Nigrostriatal: Substantia nigra to striatum
      • Mesolimbic: Ventral tegmental area (VTA) to limbic area
      • Mesocortical: Ventral tegmental area (VTA) to cortical regions
    • DA is destroyed or reuptake by:
      • Dopamine transporters (DAT)
      • Monoamine oxidase (MAO-A and MAO-B)
      • Catechol-O-methyltransferase (COMT)
  • Norepinephrine/Noradrenaline (NE/NA)
    • Also a hormone secreted by adrenal glands
    • Adrenaline or epinephrine are closely related
    • G-coupled (metabotropic) receptors (also called "adrenoceptors")
    • α1(A,B,D), α2(A,B,C), β1, β2 receptors
      • Both NE and epinephrine bind
    • α2 (also autoreceptor) is the only inhibitory receptor
    • Originates in locus coeruleus (LC, A6) and branches from there to the forebrain, cerebellum, and spinal cord
    • LC is involved in stress, arousal, sleep cycle, attention/memory, cognition, pain, mood, posture, and balance
    • NE is destroyed or reuptakeby:
      • Noradrenaline transporters (NET)
      • Monoamine oxidase (MAO-A)
      • Catechol-O-methyltransferase (COMT)
  • Serotonin (5-HT)
    • Ligand-gated (ionotropic) and G-coupled (metabotropic) receptors
    • 14 receptor subtypes (5-HT1A,B,D,F, 5-HT2A-2C, 5-HT3, 5-HT4, 5-HT5a-5B, 5-HT6, 5-HT7)
    • 5-HT1 and 5-HT5 (postsynaptic and autoreceptor) – inhibitory
    • All other G-coupled receptors are excitatory
    • Nine clusters of 5-HT neurons: most found along the midline of the brainstem
      • B6, B7: dorsal raphe
      • B5, B8: median raphe
      • B9: dorsal pontine tegmentum
      • B4: dorsal raphe obscurus
      • B1: raphe pallidus
      • B2: raphe obscurus
      • B3: raphe magnus
    • Involved in arousal, sleep (dreaming), aggression, cognition, pain, depression, and anxiety
    • 5-HT is destroyed or reuptake by:
      • 5-HT transporters (SERT)
      • Monoamine oxidase (MAO-A)
  • Histamine
    • G-coupled (metabotropic) receptors
    • Four receptor subtypes (H1-H4)
    • H3 are autoreceptors and heteroreceptors (inhibitory)
    • Neurons originate in the tuberomammillary nucleus (TMN, posterior hypothalamus) which branches to the brainstem, spinal cord, and cerebral cortex
    • Produced by mast cells and basophils (immune cells)
    • H4 is mainly on immune cells
    • Histamine is destroyed but not reuptaked by:
      • Histamine N-methyltransferase (HNMT)

Neurotransmitters

  • Dopamine is degraded by COMT in both the postsynaptic neuron and astrocytes
  • Glutamate is the primary excitatory neurotransmitter
  • Glutamate receptors are both ligand-gated (ionotropic) and G-coupled (metabotropic)
  • Glutamate metabotropic receptors (mGluR1-mGluR8) are categorized into three groups; Group I, Group II, and Group III
  • Group I mGluR receptors (mGluR1, mGluR5) are located postsynaptically and contribute to excitatory transmission
  • Group II mGluR receptors (mGluR2, mGluR3) are found both pre- and postsynaptically: they act as inhibitory autoreceptors pre-synaptically and heteroreceptors in glia
  • Group III mGluR receptors (mGluR4, mGluR6, mGluR7, mGluR8) are also found both pre- and postsynaptically: they act as inhibitory heteroreceptors in glia
  • Glutamate is removed from the synapse by excitatory amino acid transporters (EAAT1-5) and broken down into glutamine by glutamine synthase
  • GABA is the main inhibitory neurotransmitter in the nervous system
  • GABA receptors are both ligand-gated (ionotropic) and G-coupled (metabotropic)
  • GABA is synthesized from glutamate via glutamate decarboxylase (GAD)
  • Removal of GABA from the synaptic cleft is achieved by GABA transporters (GAT-1, GAT-2, GAT-3) and degradation by GABA aminotransferase (GABA-AT)
  • Acetylcholine (ACh) receptors are both ligand-gated (ionotropic) and G-coupled (metabotropic)
  • Muscarinic mACh receptors are the most common subtype of ACh receptor and are activated by muscarine.
  • Ionotropic and metabotropic ACh receptors are both activated by ACh
  • Acetylcholine has two major pathways: 1) basal forebrain projections to cortical, thalamic, and limbic sites and 2) pontine tegmental areas project to subcortical sites and spinal cord
  • Acetylcholine is also found in localized regions of the striatum and cerebellum
  • There are 5 subtypes of muscarinic receptors (M1-M5)
  • M1, M3, and M5 are excitatory, while M2 and M4 are inhibitory
  • ACh is degraded by acetylcholinesterase (AChE)

Peptides and Lipids

  • Peptides can act as neuromodulators and neurotransmitters
  • Peptides can act both through the synaptic cleft and diffuse to other neurons or cells
  • Peptides are degraded by a variety of enzymes but are not reuptaken
  • Examples of peptides include opioids (enkephalins, dynorphins, β-endorphins), substance P, calcitonin gene-related peptide (CGRP), somatostatin, and neuropeptide Y
  • Lipids are released through the lipid membrane (not vesicles), typically in the postsynaptic neuron
  • Lipids mediate retrograde transmissions (communication from post-synaptic to pre-synaptic)
  • Example lipids include endocannabinoids such as anandamide (AEA) and 2-arachidonyl glycerol (2-AG)
  • Lipids are degraded by a variety of enzymes and reuptaken by different transporters

Drug Discovery

  • Modern drug discovery involves a trial-and-error approach
  • The first step in drug discovery is identifying the disease to be treated
  • Target identification focuses on finding a mechanism involved in disease pathophysiology
  • Targets can include receptors, neurotransmitters, reuptake systems, cytokines, and ion channels

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Pharmacology Lecture 2 Notes on Glia, Communication and Transmitters

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Test your knowledge on metabotropic receptors and the second messenger system in neuroscience. This quiz covers their functions, mechanisms, and the role of neurotransmitters in neuronal signaling. Explore how these concepts are essential for understanding synaptic transmission and neuron modulation.

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