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Questions and Answers
Considering the allosteric modulation of $GABA_A$ receptors, which of the following scenarios would MOST effectively potentiate the inhibitory effects of GABA, assuming equivalent concentrations of all modulators at their respective binding sites?
Considering the allosteric modulation of $GABA_A$ receptors, which of the following scenarios would MOST effectively potentiate the inhibitory effects of GABA, assuming equivalent concentrations of all modulators at their respective binding sites?
- Administration of an anxiolytic drug that selectively enhances GABA affinity at synaptic receptors combined with a competitive GABA antagonist to prevent over-inhibition
- Concurrent application of a barbiturate that prolongs the GABA-induced chloride ion channel opening time and an antagonist at the benzodiazepine binding site.
- Exposure to an intravenous anesthetic at a concentration that primarily targets extrasynaptic $GABA_A$ receptors in conjunction with a GABA uptake inhibitor.
- Simultaneous administration of a neurosteroid that increases the duration of channel opening and a benzodiazepine that increases the frequency of channel opening. (correct)
In the context of ligand-gated ion channels (LGICs), which of the following biophysical properties would MOST critically determine the reversal potential of a postsynaptic response mediated by a heteromeric pentameric receptor composed of distinct subunits?
In the context of ligand-gated ion channels (LGICs), which of the following biophysical properties would MOST critically determine the reversal potential of a postsynaptic response mediated by a heteromeric pentameric receptor composed of distinct subunits?
- The phosphorylation state of intracellular loop domains, modulating downstream signaling pathways.
- The specific arrangement and electrostatic properties of amino acid residues lining the pore-forming region contributed by each subunit. (correct)
- The glycosylation patterns on the extracellular loops, influencing the binding affinity for agonists.
- The number of charged amino acid residues within the extracellular N-terminal domain.
A researcher is investigating a novel ligand-gated ion channel (LGIC) found to be trimeric. Based on established LGIC structural families, which of the following features would be MOST unexpected?
A researcher is investigating a novel ligand-gated ion channel (LGIC) found to be trimeric. Based on established LGIC structural families, which of the following features would be MOST unexpected?
- Functional modulation by allosteric modulators acting on the extracellular domain.
- Each subunit contributes transmembrane domains arranged to form a central ion-conducting pore.
- The presence of a large extracellular domain responsible for ligand binding.
- Significant sequence homology to subunits of the Cys-loop receptor family. (correct)
A novel mutation in the M2 transmembrane domain of the α7 nicotinic acetylcholine receptor subunit is discovered. Functional studies reveal that the mutant receptor exhibits constitutive channel activity even in the absence of acetylcholine. Which structural alteration is MOST likely responsible for this gain-of-function phenotype?
A novel mutation in the M2 transmembrane domain of the α7 nicotinic acetylcholine receptor subunit is discovered. Functional studies reveal that the mutant receptor exhibits constitutive channel activity even in the absence of acetylcholine. Which structural alteration is MOST likely responsible for this gain-of-function phenotype?
Given the diversity of $GABA_A$ receptor subunit composition, which of the following combinations would be MOST likely to mediate tonic inhibition in hippocampal pyramidal neurons, considering their typical localization and affinity for GABA?
Given the diversity of $GABA_A$ receptor subunit composition, which of the following combinations would be MOST likely to mediate tonic inhibition in hippocampal pyramidal neurons, considering their typical localization and affinity for GABA?
Considering the role of ligand-gated ion channels in synaptic transmission, which of the following scenarios would MOST effectively impair long-term potentiation (LTP) at glutamatergic synapses, assuming interventions are highly specific?
Considering the role of ligand-gated ion channels in synaptic transmission, which of the following scenarios would MOST effectively impair long-term potentiation (LTP) at glutamatergic synapses, assuming interventions are highly specific?
Within the structural context of Cys-loop receptors, what is the MOST critical functional consequence of the conserved disulfide bond within the 'Cys-loop' region of the N-terminal extracellular domain?
Within the structural context of Cys-loop receptors, what is the MOST critical functional consequence of the conserved disulfide bond within the 'Cys-loop' region of the N-terminal extracellular domain?
If a novel compound selectively disrupts the interaction between the intracellular loop of a $GABA_A$ receptor subunit and the postsynaptic scaffolding protein gephyrin, which immediate electrophysiological consequence would MOST likely be observed?
If a novel compound selectively disrupts the interaction between the intracellular loop of a $GABA_A$ receptor subunit and the postsynaptic scaffolding protein gephyrin, which immediate electrophysiological consequence would MOST likely be observed?
In the context of P2X receptors, what is the MOST significant implication of their trimeric quaternary structure on their pharmacological properties, particularly concerning non-selective antagonists?
In the context of P2X receptors, what is the MOST significant implication of their trimeric quaternary structure on their pharmacological properties, particularly concerning non-selective antagonists?
If a researcher discovers that a particular $GABA_A$ receptor subtype exhibits significantly slower desensitization kinetics compared to other subtypes, which structural feature is MOST likely responsible for this difference?
If a researcher discovers that a particular $GABA_A$ receptor subtype exhibits significantly slower desensitization kinetics compared to other subtypes, which structural feature is MOST likely responsible for this difference?
A research team is trying to design a $GABA_A$ receptor agonist that selectively targets extrasynaptic receptors. Which strategy is MOST promising?
A research team is trying to design a $GABA_A$ receptor agonist that selectively targets extrasynaptic receptors. Which strategy is MOST promising?
Which of the following best describes the subunit arrangement for muscle-type (NM) nicotinic acetylcholine receptors?
Which of the following best describes the subunit arrangement for muscle-type (NM) nicotinic acetylcholine receptors?
If researchers found that a particular mutation in the nicotinic acetylcholine receptor increased the rate of desensitization, which structural change is MOST likely to cause this?
If researchers found that a particular mutation in the nicotinic acetylcholine receptor increased the rate of desensitization, which structural change is MOST likely to cause this?
Which of the following characteristics is LEAST likely to be associated with neuronal nicotinic acetylcholine receptors located in the central nervous system (CNS)?
Which of the following characteristics is LEAST likely to be associated with neuronal nicotinic acetylcholine receptors located in the central nervous system (CNS)?
A research group discovers a novel compound that selectively inhibits P2X receptors. Which of the following mechanisms is MOST likely to explain its selectivity?
A research group discovers a novel compound that selectively inhibits P2X receptors. Which of the following mechanisms is MOST likely to explain its selectivity?
If a mutation in a ligand-gated ion channel resulted in a loss of sensitivity to benzodiazepines, which subunit is MOST likely affected?
If a mutation in a ligand-gated ion channel resulted in a loss of sensitivity to benzodiazepines, which subunit is MOST likely affected?
Which of the following BEST describes the structural difference between ionotropic glutamate receptors and other ligand-gated ion channel families like the Cys-loop receptors:
Which of the following BEST describes the structural difference between ionotropic glutamate receptors and other ligand-gated ion channel families like the Cys-loop receptors:
Which of the following is MOST accurate regarding the functional consequence of phosphorylation of intracellular domains in ligand-gated ion channel subunits?
Which of the following is MOST accurate regarding the functional consequence of phosphorylation of intracellular domains in ligand-gated ion channel subunits?
In the context of ligand-gated ion channels, what distinguishes 'phasic' from 'tonic' inhibition mediated by GABAA receptors?
In the context of ligand-gated ion channels, what distinguishes 'phasic' from 'tonic' inhibition mediated by GABAA receptors?
How would an increased concentration of extracellular ATP MOST directly impact neuronal excitability, considering its role in activating ligand-gated ion channels?
How would an increased concentration of extracellular ATP MOST directly impact neuronal excitability, considering its role in activating ligand-gated ion channels?
Flashcards
Receptor Superfamily
Receptor Superfamily
A group of receptors sharing a similar molecular structure and utilizing the same signal transduction pathway.
Ligand-Gated Ion Channels (LGICs)
Ligand-Gated Ion Channels (LGICs)
A major receptor superfamily that opens depending on the gradient change, facilitating ion exchange.
Signal Transduction via LGICs
Signal Transduction via LGICs
The process by which LGICs convert a signal into a cellular response by ion flow.
Excitatory LGICs
Excitatory LGICs
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Inhibitory LGICs
Inhibitory LGICs
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Cys-loop Receptor Family
Cys-loop Receptor Family
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Ionotropic Glutamate Receptors
Ionotropic Glutamate Receptors
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P2X Receptor Family
P2X Receptor Family
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Nicotinic Acetylcholine Receptor (nAChR)
Nicotinic Acetylcholine Receptor (nAChR)
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Muscle (NM) nAChR Subtype
Muscle (NM) nAChR Subtype
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Neuronal (NN) nAChR Subtype
Neuronal (NN) nAChR Subtype
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GABAA Receptor
GABAA Receptor
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Synaptic GABAA receptors
Synaptic GABAA receptors
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Extrasynaptic GABAA receptors
Extrasynaptic GABAA receptors
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Allosteric Modulation of GABAA Receptors
Allosteric Modulation of GABAA Receptors
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Study Notes
- Receptor superfamilies are groups of receptors sharing a similar basic molecular structure and utilizing the same signal transduction pathway
- There are four major receptor superfamilies: ligand-gated ion channel-linked, G-protein-coupled, kinase-linked, and intracellular/nuclear receptors
Ligand-Gated Ion Channels (LGICs)
- LGICs open depending on the gradient change, allowing for ion exchange
- LGICs constitute a diverse superfamily of multimeric integral membrane receptor proteins
- These proteins incorporate extracellular ligand-binding sites for ligands like hormones or neurotransmitters
- They also include a central transmembrane ion-permeable channel/pore for ions like sodium
- Ligand binding induces a conformational change, opening the ion-permeable pore.
- The opening of the pore allows ions to flow into or out of the cell down their electrochemical gradient
- The ion flow modulates cellular function, leading to a biological response
- LGICs mediate synaptic transmission, neural communication, cell excitation, muscle contraction, and intracellular signaling
LGIC Subclassification
- LGICs are subclassified based on the impact of ion flow through the open channel on membrane potential and cellular electrical activity
- Excitatory LGICs include nAChR, 5-HT3R, ionotropic glutamate receptors (NMDA, AMPA & kainate), and P2X receptors
- Excitatory LGICs facilitate cation influx, leading to membrane depolarization
- Inhibitory LGICs, such as GABAAR and glycine receptors, mediate anion influx
- Anion influx leading to membrane hyperpolarization and reduced neuronal response probability
LGIC Molecular Structure and Subunit Stoichiometry
- Cys-loop receptors are pentameric, composed of 5 subunits including nAChR, 5-HT3R, GABAAR, and glycine receptors
- Ionotropic glutamate receptors are tetrameric, composed of 4 subunits including NMDA, AMPA, and kainate receptors
- P2X receptors are trimeric, composed of 3 subunits and are purinergic, with ATP as a ligand, including P2X1-7 receptors
LGIC Molecular Architecture: Cys-Loop Receptors
- Functional receptors consist of 5 subunits arranged around a central ion-conducting pore
- Subunits have a common structure: a large N-terminal extracellular domain, four transmembrane alpha-helices (M1-M4), and a short extracellular C-terminal domain
- The N-terminal domain contains the ligand-binding site and a signature disulphide Cys-loop
- The transmembrane helices (M1-M4) line the ion-conducting pore
LGIC Molecular Architecture: Ionotropic Glutamate Receptors
- Functional receptors are composed of 4 subunits arranged around a central ion-conducting pore
- Each subunit is an integral membrane protein with: a large extracellular N-terminal domain, 3 membrane-spanning domains (M1, M3 and M4), a hydrophobic hairpin domain (M2), and 3 intracellular domains
- Subunits create non-selective cation channels gated by glutamate
LGIC Molecular Architecture: P2X Receptors
- Functional receptors are composed of 3 subunits arranged around a central ion-conducting pore
- Each subunit contains 2 transmembrane domains (TM1 & TM2) separated by an extracellular ligand-binding domain and intracellular amino and carboxyl termini
- Seven receptor subunits (P2X1-7) co-assemble into homo- or hetero-trimeric channels that are non-selective and gated by extracellular ATP
Nicotinic Acetylcholine Receptor (nAChR)
- nAChR is a prototypical Cys-loop ligand-gated receptor activated by acetylcholine
- Nicotine also activates nAChRs, hence its name
- They mediate fast synaptic transmission in the nervous system and at the somatic neuromuscular junction (NMJ), causing skeletal muscle contraction
- Occur in pre- and post-synapses
- ACh binding leads to Na+ influx, membrane depolarization, Ca++ influx, and neurotransmitter release (CNS) or fast post-synaptic excitation
- nAChRs regulate skeletal muscle contraction, neuronal excitability, gene expression, learning, memory, and neuroprotection
nAChR Structure and Subtypes
- Two distinct nAChR subtypes exist: muscle (NM) and neuronal (NN)
- NM subtype is at the neuromuscular junction (NMJ), while NN subtype is at autonomic ganglia and in the CNS
- Both are pentameric, composed of 5 subunits
- There are 17 nAChR subunits, including ten ɑ (ɑ1 to ɑ10) and four β (β1 to β4) isoforms
- Muscle (NM) subtypes typically consist of 2 α1, β1, δ, and γ/ε subunits
- Neuronal (NN) subtypes consist of either 2 α and 3 β subunits (hetero-pentamers) or 5 α7 subunits (homo-pentamers)
nAChR Muscle Type
- Five M2 ɑ-helices form and line the ion-conducting pore center
- There are two ACh binding sites at the interface between the two ɑ subunits and neighboring δ & γ/ε subunits
- Two ACh molecules must bind for receptor activation
nAChR Functional Roles
- In the autonomic nervous system (PNS), Muscle (NM) subtypes mediate fast excitatory synaptic transmission and skeletal muscle contraction at the neuromuscular junction (NMJ)
- Neuronal (NN) subtypes mediate fast excitatory synaptic transmission and autonomic control of peripheral organs post-synaptically
- In the central nervous system (CNS), neuronal (NN) subtypes modulate transmitter release, neuronal excitability/integration, gene expression, differentiation/survival, cognition, learning, memory, and neuroprotection
Role of Muscle Type (NM) nAChRs
- NM receptors in skeletal muscle contraction cause massive depolarization via voltage-gated sodium channels, leading to massive sodium influx
GABA A Receptor
- GABA A Receptor is a major inhibitory neurotransmitter in the brain
- A class of Cys-loop ligand-gated receptor ion channels
- Activated by γ-aminobutyric acid (GABA)
- Channel opening increases Cl- influx, causing membrane hyperpolarization, resulting in fast post-synaptic inhibition
- Gating is allosterically modulated by drugs and chemicals like benzodiazepines and alcohol
- GABA A Receptors are widespread in the CNS, mediating fast (phasic) and tonic post-synaptic inhibition
GABA A Receptor Structure and Function
- Receptor proteins are pentamers composed of 5 subunits
- There are 8 subunit classes cloned: ɑ1-6, β1-3, γ1-3, δ, ε, θ, π, 𝜌1-3
- Subunits co-assemble to form homo- or hetero- pentameric receptors
- Functional receptors are formed from two α-subunits and two β-subunits, plus a γ- or δ-subunit
- Subunit composition depends on the location of receptor and the GABA binding sites are located at α/β subunit interfaces
GABA A Receptor Localisation, Subtypes & Function
- Synaptic receptors are found post-synaptically at synaptic sites, contain a γ-subunit and ɑ1, ɑ2, or ɑ3 subunits
- Activated by synaptically released GABA & medicate phasic inhibition & have lower affinity for GABA (binds to benzodiazepines)
- Extrasynaptic receptors are found post-synaptically but outside of synaptic sites
- Contain a δ-subunit and a4, a5, or a6 subunits, activated by GABA spillover & mediate tonic inhibition, higher affinity for GABA & low benzodiazepine sensitivity
- Preferentially modulate propofol, neurosteroids, and ethanol
GABA A Receptor Roles
- Widespread distribution in the brain includes high densities in the cerebral cortex, hippocampus, & cerebellum
- Has CNS effects, including fast (phasic) & slow (tonic) neuronal inhibition, control of feeding behavior, circadian rhythm, and implicated in numerous disorders
GABA A Receptor as Drug Target
- Receptors have multiple ligand binding sites, and are major targets for a large class of therapeutic & recreational drugs
- Drugs include benzodiazepines, barbiturates, neurosteroids, general anaesthetics, and alcohol
- These bind to allosteric binding sites, and enhance the effects of GABA (known as positive allosteric modulation) on the receptor
- Allosteric binding leads to channel opening and Cl- influx, resulting in increased membrane hyperpolarization and neuronal inhibition
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