Neurotransmitter Receptors II: Metabotropic Focus
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Questions and Answers

What role does the second intracellular loop (i2) play in mGluR functions?

  • It enhances AMPAR activation.
  • It functions independently of ion influx.
  • It facilitates fast synaptic transmission.
  • It is essential for G-protein coupling. (correct)

Which type of mGluR primarily activates Gq signaling?

  • Class II mGluRs
  • Class III mGluRs
  • All metabotropic receptors
  • Class I mGluRs (correct)

What is the result of mGluR1 activation?

  • Induces fast EPSC predominantly.
  • Leads to AMPAR-independent synaptic transmission.
  • Causes a slow EPSC through TRPC3 activation. (correct)
  • Inhibits the influx of Ca2+.

What primarily mediates calcium influx during mGluR1 signaling?

<p>TRPC3 activation (C)</p> Signup and view all the answers

Which of the following statements about fast and slow EPSCs is true?

<p>Only slow EPSCs rely on TRPC3. (B)</p> Signup and view all the answers

What potential mechanism does the C-terminal domain of mGluRs contribute to?

<p>G-protein interaction facilitation (A)</p> Signup and view all the answers

Which ion's levels increase as a result of TRPC3 activation during mGluR1 signaling?

<p>Ca2+ (C)</p> Signup and view all the answers

In the context of mGluRs, what does EPSC stand for?

<p>Excitatory Post Synaptic Current (A)</p> Signup and view all the answers

What ion channels are activated by the increase in DAG levels resulting from mGluR1-mediated voltage-gated calcium channels?

<p>TRPC3 channels (C)</p> Signup and view all the answers

What is the primary action of Class II mGluRs on calcium influx?

<p>Attenuates Ca2+ influx (C)</p> Signup and view all the answers

Where are Class III mGluRs predominantly located?

<p>On presynaptic terminals of glutamatergic and GABAergic neurons (A)</p> Signup and view all the answers

What type of proteins do Class II mGluRs couple to?

<p>Gi/o proteins (C)</p> Signup and view all the answers

What is the primary effect of the activation of mGluR1 on dendritic signaling?

<p>Slow depolarization of the neuron (B)</p> Signup and view all the answers

What is the primary role of mGluRs in the brain's neurotransmission?

<p>Modulating both excitatory and inhibitory neurotransmission (B)</p> Signup and view all the answers

Which of the following is NOT a characteristic of Class II mGluRs?

<p>Increase neurotransmitter release (A)</p> Signup and view all the answers

What ionic activities are associated with TRPC3 channel activation?

<p>Simultaneous Na+ and Ca2+ conductance (C)</p> Signup and view all the answers

Which muscles contain the highest expression of M1 muscarinic ACh receptors?

<p>Cerebral cortex (D)</p> Signup and view all the answers

What is the primary role of presynaptic M1Rs in neurotransmission?

<p>Facilitate ACh release (D)</p> Signup and view all the answers

Which of the following is NOT a major type of muscarinic ACh receptor mentioned?

<p>M6 (D)</p> Signup and view all the answers

What mechanism is primarily activated by postsynaptic M1Rs?

<p>Slow postsynaptic depolarization (C)</p> Signup and view all the answers

Which G protein is associated with the activation of presynaptic M1Rs?

<p>Gq (B)</p> Signup and view all the answers

How do M2 and M4 muscarinic receptors primarily function within the brain?

<p>Presynaptic inhibitory receptors (C)</p> Signup and view all the answers

What is the outcome of activating postsynaptic M1Rs in terms of neuronal activity?

<p>Increased neuronal excitability (B)</p> Signup and view all the answers

Which of the following describes the expression pattern of M3 and M5 muscarinic receptors?

<p>Significantly lower levels than M1 (D)</p> Signup and view all the answers

What is the primary mechanism by which agonist binding affects GPCR conformation?

<p>It stabilizes the active conformation. (A)</p> Signup and view all the answers

What characterizes negative antagonism in GPCR signaling?

<p>It impedes the transition to the active state. (B)</p> Signup and view all the answers

Which type of GPCR is primarily associated with muscarinic acetylcholine receptors?

<p>mAChRs (A)</p> Signup and view all the answers

What role does the i3 region play in GPCR activation?

<p>It is essential for G-protein coupling and activation. (D)</p> Signup and view all the answers

What effect does antagonist binding have on GPCRs?

<p>It prevents further transition to either state. (B)</p> Signup and view all the answers

Which of the following describes the function of mGluRs?

<p>They are metabotropic glutamate receptors. (A)</p> Signup and view all the answers

What does GPCR desensitization refer to?

<p>It reduces receptor signaling efficacy. (A)</p> Signup and view all the answers

Which of the following is NOT a type of GPCR mentioned?

<p>ADH receptors (C)</p> Signup and view all the answers

How do GPCRs mainly transmit signals?

<p>By activating downstream effector proteins. (C)</p> Signup and view all the answers

What is a key feature of G protein coupling?

<p>It is highly selective and efficient. (B)</p> Signup and view all the answers

What is the role of GABA B2 in relation to GABA B1?

<p>It stabilizes the agonist-bound conformation of GABA B1. (C)</p> Signup and view all the answers

What happens to cAMP levels when Gi/o proteins are activated?

<p>cAMP levels decrease. (D)</p> Signup and view all the answers

Which of the following mechanisms is primarily responsible for preventing neurotransmitter release at presynaptic sites?

<p>Inhibition of SNARE complex proteins. (D)</p> Signup and view all the answers

How does GABA B2 contribute to G protein coupling?

<p>By stabilizing GABA B1's conformation. (A)</p> Signup and view all the answers

What is the primary effect of Gβγ-mediated inhibition of voltage-dependent calcium channels?

<p>It reduces intracellular calcium influx. (B)</p> Signup and view all the answers

What would be the consequence of inhibiting voltage-dependent calcium channels in presynaptic neurons?

<p>Decreased neurotransmitter release. (D)</p> Signup and view all the answers

What is the overall effect of GABAB receptor activation on synaptic transmission?

<p>Inhibits neurotransmitter release. (D)</p> Signup and view all the answers

Which G protein subunit is directly involved in the inhibition of adenylyl cyclase?

<p>Gα subunits. (D)</p> Signup and view all the answers

What initiates endocytosis of GPCRs?

<p>Conformational change in b-arrestin (D)</p> Signup and view all the answers

After endocytosis, what is the primary function of protein phosphatases on GPCRs?

<p>To dephosphorylate the GPCRs (C)</p> Signup and view all the answers

What role does AP2 play in the endocytosis of GPCRs?

<p>It assists in the formation of clathrin-coated pits (D)</p> Signup and view all the answers

What occurs to GPCRs in the sorting endosome?

<p>GPCRs are targeted either for recycling or degradation (B)</p> Signup and view all the answers

Which type of endocytic vesicle does not recycle GPCRs?

<p>Lysosomal vesicles (B)</p> Signup and view all the answers

Which event directly follows the binding of GPCRs to their ligands?

<p>Conformational change in the GPCR (C)</p> Signup and view all the answers

What is the immediate consequence of GPCR desensitization?

<p>Decrease in receptor sensitivity to ligands (D)</p> Signup and view all the answers

The interaction of which protein with GPCRs promotes endocytosis?

<p>b-arrestin (A)</p> Signup and view all the answers

Flashcards

GPCR activation

Ligand binding to a GPCR (G protein-coupled receptor) causes a conformational change, activating the receptor.

G protein activation

Activated GPCRs trigger the activation of associated G proteins.

Antagonist binding

A molecule that blocks the activation of a GPCR by preventing the receptor from changing shape.

Effector mechanisms (presynaptic)

Processes happening before transmission of the signal across the synapse.

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Effector mechanisms (postsynaptic)

Processes happening after the transmission of the signal across the synapse.

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GPCR types

Different types of GPCRs exist, each with specific functions, such as mGluRs, mAChRs, GABABRs.

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GPCR desensitization

The process by which GPCR activity diminishes over time.

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Ligand-induced conformational changes

The shape of a GPCR changes when a ligand binds to it, triggering a cascade of events.

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Specificity and efficiency of G protein coupling

The precise way certain G proteins attach to GPCRs, ensuring a particular signal transduction pathway occurs.

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GPCR General Structure

A transmembrane protein that spans the cell membrane seven times.

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mGluR1 activation

Leads to a slow excitatory postsynaptic current (EPSC).

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mGluR1 sEPSC

A slow excitatory postsynaptic current (EPSC) initiated by mGluR1 activation.

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i2 (intracellular loop 2)

Plays a role in G-protein coupling for metabotropic glutamate receptors (mGluRs).

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mGluRs

Metabotropic glutamate receptors are a group of G protein-coupled receptors that mediate slower responses to glutamate.

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Class I mGluRs

A class of mGluRs predominantly located in postsynaptic membranes primarily activating Gq signaling pathways.

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TRPC3 activation leads to

Increased levels of Ca2+ leading to an effect on slow EPSC.

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Fast EPSC

AMPAR-dependent excitatory postsynaptic current (EPSC) with rapid onset.

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Slow EPSC

A relatively slower EPSC often mediated by mGluR-TRPC3 interaction, which takes time to fully develop.

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mGluR1 activation

Activation of mGluR1 receptors leads to increased DAG levels, activating TRPC3 channels, which allow Na+ and Ca2+ to enter the cell.

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TRPC3 channel

A type of ion channel permeable to Na+ and Ca2+, activated by the increased DAG levels downstream of mGluR1 activation.

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DAG

A molecule that serves as a secondary messenger, increasing in concentration following mGluR1 activation, triggering TRPC3 activation.

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Class II mGluRs

Metabotropic glutamate receptors that couple to Gi/o proteins, inhibiting AC (adenylyl cyclase) and reducing Ca2+ influx.

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Gi/o proteins

Intracellular signaling proteins that mediate the effects of metabotropic glutamate receptors (mGluRs), including modulation of adenyl cyclase (AC).

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mGluR Activation Effects

Activation of mGluRs can influence both neurotransmitter release and membrane potential.

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Class III mGluRs

mGluRs that couple to Gi/o proteins, modulating presynaptic terminals of both glutamatergic and GABAergic neurons.

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Membrane Potential Change

Changes in the membrane potential due to ion movement, often occurring during an action potential or synaptic transmission.

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Muscarinic ACh Receptors (mAChRs)

A family of receptors that bind acetylcholine (ACh), influencing both pre- and postsynaptic processes.

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Presynaptic mAChRs

mAChRs located before the synapse that regulate ACh release.

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Postsynaptic mAChRs

mAChRs located after the synapse that affect postsynaptic cells.

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M1R mAChR subtype

A key postsynaptic mAChR subtype, highly expressed in the cortex, hippocampus, and striatum.

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M1R activation (presynaptic)

Increases intracellular Ca2+ levels, leading to ACh release.

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M1R activation (postsynaptic)

Causes slow depolarization and increased neuronal excitability.

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M2 and M4 mAChRs

Predominant presynaptic mAChRs regulating ACh release.

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mGluRs, mAChRs, GABABRs

Different types of GPCRs (G-protein coupled receptors) each influencing specific signaling pathways.

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GABA B2 Receptor Interaction

GABA B2 receptor interacts with GABA B1, stabilizing its agonist-bound conformation, increasing agonist affinity.

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GPCR Endocytosis

GPCRs (G protein-coupled receptors) are internalized into the cell via clathrin-coated pits, then recycled or degraded.

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b-arrestin role

b-arrestin binds to activated GPCRs, triggering endocytosis.

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GABA B Receptor Coupling

GABA B receptors are responsible for activating G protein.

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Gi/o protein activation Effect

Activation of Gi/o protein inhibits neurotransmitter release.

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GPCR Dephosphorylation

GPCRs are dephosphorylated in the sorting endosome by protein phosphatases.

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Adenylyl Cyclase Inhibition

Gi subunits reduce cAMP levels by inhibiting adenylyl cyclase.

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Sorting Endosome Pathways

GPCRs can be sent to recycling vesicles for reuse or to lysosomes for degradation.

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Voltage-Dependent Calcium Channel Inhibition

Gβγ subunits inhibit voltage-dependent calcium channels (VDCCs).

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Ionotropic vs. Metabotropic

Different signal transduction pathways for neurotransmitters: ionotropic direct channel opening, metabotropic pathways involving G-proteins.

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GPCR General Structure

Transmembrane protein with seven transmembrane domains.

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SNARE Complex Inhibition

Gβγ subunits inhibit SNARE complex proteins, preventing neurotransmitter release.

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Effector Mechanisms

The cell processes at the synapse (pre-synaptic and post-synaptic) influenced by GPCR signaling.

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VDCCs and Neurotransmitter Release

Depolarization activates VDCCs, causing calcium influx. Calcium triggers exocytosis.

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Gβγ-mediated inhibition

Gβγ subunits decrease neurotransmitter release by inhibiting VDCCs.

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Endocytosed GPCRs

Internalised GPCRs are directed to recycling pathways or lysosomes for degradation.

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Study Notes

Neurotransmitter Receptors II: Metabotropic Receptors

  • Metabotropic receptors are G protein-coupled receptors (GPCRs)
  • They are involved in neurotransmission
  • They have seven transmembrane domains
  • Activation of these receptors is initiated by neurotransmitters binding
  • They mediate slower, longer-lasting responses in comparison to ionotropic receptors

The Life Cycle of Neurotransmission

  • I. Synthesis (1-2): Neurotransmitters are created in the neuron.
  • II. Storage (3): Neurotransmitters are stored in vesicles within the neuron.
  • III. Release: Neurotransmitters are released from the presynaptic neuron into the synaptic cleft.
  • IV. Receptor Binding (4-5): The neurotransmitters bind to receptors on the postsynaptic neuron.
  • V. Transmitter Inactivation (6-9): Excess neurotransmitters are either broken down or reabsorbed by the presynaptic neuron.

Ionotropic vs. Metabotropic Actions

  • GPCR General Structure: GPCRs are single polypeptide chains with seven membrane-spanning helical segments wrapped through the membrane.
  • GPCR Activation and Action: Includes binding to G proteins.
  • Effector Mechanisms: Presynaptic and Postsynaptic: Specify the mechanisms of action for pre- and post-synaptic actions.
  • GPCR Types and Specific Mechanisms: Includes mGluRs, mAChRs, GABABRs, Dopamine and Serotonin receptors.
  • GPCR Desensitization: Describes how receptors lose sensitivity and function over time.

Common G protein Effector Targets

  • cAMP system: Norepinephrine and ACh activate the cAMP system, which leads to protein activation.
  • Phosphoinositol system: Involves ACh and norepinephrine triggering cascades that result in various downstream effects.

Ligand-induced GPCR Conformational Changes Activate G proteins

  • Agonist binding creates a conformational shift in the GPCR, inducing an active state.
  • The shift facilitates an interaction with G proteins.
  • Conformational changes enable activation of particular downstream pathways.

General Mechanisms of GPCR Modulation of Synaptic Transmission

  • Presynaptic GPCRs: Neurotransmitter Release
    • Gα: Modifies neurotransmitter release via PKA and PKC targets. This occurs due to modulation of proteins involved in vesicle recruitment, docking, and fusion. In turn, this can either inhibit or facilitate synaptic transmission.
    • Gβγ: Inhibits voltage-dependent calcium channels and regulates GIRK channels.
  • Presynaptic GPCRs: Neurotransmitter Release
    • Gβγ: Inhibits voltage-dependent calcium channels and regulates GIRK channels.
    • Inhibition of SNARE complex.
    • Regulation of G protein-gated inward-rectifier K+ channel (GIRK) channels.

Postsynaptic GPCRs: Excitability

  • PKA-mediated closure of K+ channels.
  • Changes in transcription and chromatin structure, e.g., PKA activation of CREB.

Dopamine Metabotropic Receptors

  • D1-like receptors: Stimulate cAMP production and activate further downstream pathways.
  • D2-like receptors: Inhibit cAMP production and activate different signaling cascades.

Serotonin Metabotropic Receptors

  • Diverse families of serotonin receptors, each leading to specific effects based on activation pathways.
  • Function predominantly as postsynaptic receptors.

GPCR Desensitization

  • Heterologous desensitization: Desensitization of receptors occurs without ligand binding.
  • Activation by GPCR kinases (GRKs) and interactions with arrestin disengage the G-protein.
  • Homologous desensitization: Desensitization requiring ligand binding.
  • Phosphorylation by GRKs triggers ẞ-arrestin binding, promoting GPCR internalization.

Overview

  • Provides a general summary connecting different sections.

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Description

This quiz delves into the specifics of metabotropic receptors, examining their role in neurotransmission and comparison to ionotropic receptors. Learn about the life cycle of neurotransmission, from synthesis to inactivation, while gaining insights into the structure and function of G protein-coupled receptors.

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