Week 32 /Ligand-Gated Ion Channels Flashcards
Q: What is a receptor superfamily?
A: A group of receptors with a similar basic molecular structure that use the same signal transduction pathway.
Q: What are the four major receptor superfamilies?
A:
Ligand-gated (ion channel-linked) receptors
G-protein-coupled receptors
Kinase-linked receptors
Intracellular (nuclear) receptors
Q: What are Ligand-Gated Ion Channels (LGICs)?
A: A diverse superfamily of multimeric integral membrane receptor proteins with extracellular ligand-binding sites and a central ion-permeable channel.
Q: What happens when a ligand (neurotransmitter) binds to an LGIC?
A: It causes a conformational change in the receptor, opening the ion-permeable pore, allowing ions to flow down their electrochemical gradient.
Q: What are some biological functions of LGICs?
A: Synaptic transmission, neural communication, cell excitation, muscle contraction, and intracellular signaling.
Q: How are Ligand-Gated Ion Channels (LGICs) subclassified?
A: Based on their effect on membrane potential and cellular electrical activity due to ion flow.
Q: How does ion flow through LGICs affect the cell?
A: It modulates cellular function, leading to a biological response.
Q: What are excitatory, cation-selective LGICs?
A: Receptors such as nAChR, 5-HT₃R, ionotropic glutamate (NMDA, AMPA, kainate) receptors, and P2X receptors that mediate cation influx, causing membrane depolarization.
Q: What are inhibitory, anion-selective LGICs?
A: Receptors like GABAᴀ and glycine receptors that mediate anion influx, causing membrane hyperpolarization.
Q: How can Ligand-Gated Ion Channels (LGICs) be subclassified based on molecular structure?
A: They are classified by their subunit stoichiometry into three families: Cys-loop receptors, ionotropic glutamate receptors, and P2X receptors.
Q: What is the structure of the Cys-loop receptor family, and which receptors belong to it?
A: Pentameric (5 subunits); includes nAChR, 5-HT₃R, GABAᴀR, and glycine receptors.
Q: What is the structure of the ionotropic glutamate receptor family, and which receptors belong to it?
A: Tetrameric (4 subunits); includes NMDA, AMPA, and kainate receptors.
Q: What is the structure of the P2X receptor family, and which receptors belong to it?
A: Trimeric (3 subunits); includes P2X₁, P2X₂, P2X₃, P2X₄, P2X₅, and P2X₇ receptors.
Q: What is the structural composition of Cys-loop receptor family members?
A: They are pentameric receptors composed of five subunits arranged around a central ion-conducting pore.
Q: What are the key structural features of Cys-loop receptors?
A:
Large N-terminal extracellular domain – contains the ligand-binding site and the signature Cys-loop (disulfide bond).
Four transmembrane α-helices (M1-M4) – line the ion-conducting pore.
Short extracellular C-terminal domain.
Q: What are some examples of Cys-loop receptors?
A: nAChR, 5-HT₃R, GABAᴀR, and glycine receptors.
Q: What is the structural composition of ionotropic glutamate receptors?
A: They are tetrameric receptors composed of four subunits arranged around a central ion-conducting pore.
Q: What are the key structural features of ionotropic glutamate receptor subunits?
A:
Large extracellular N-terminal domain.
Three membrane-spanning domains (M1, M3, M4).
A hydrophobic hairpin domain (M2) that forms/lines the ion channel pore.
Three intracellular domains: Loop1, Loop2, and the carboxyl tail.
Q: What type of ions do ionotropic glutamate receptors conduct?
A: They are non-selective cation channels that are gated by glutamate.
Q: What is the structural composition of P2X receptors?
A: They are trimeric receptors composed of three subunits arranged around a central ion-conducting pore.
Q: What are the key structural features of P2X receptor subunits?
A:
Two transmembrane domains (TM1 & TM2).
A large extracellular ligand-binding domain (‘ectodomain’).
Intracellular N-terminal and C-terminal domains.
Q: How many P2X receptor subunits exist in mammals, and how do they assemble?
A: There are seven subunits (P2X₁-P2X₇) that can form homo- or hetero-trimeric channels.
Q: What activates P2X receptors, and what type of ions do they conduct?
A: They are gated by extracellular ATP and function as non-selective cation channels.
Q: What type of receptor is the Nicotinic Acetylcholine Receptor (nAChR)?
A: It is a prototypical Cys-loop ligand-gated receptor activated by acetylcholine (ACh) and nicotine.
Q: Where are nAChRs located in the body?
A: They are found in the central and peripheral nervous system, mediating fast synaptic transmission in the nervous system and at the neuromuscular junction (NMJ).
Q: What happens when ACh binds to nAChR?
A:
Channel opens, allowing Na⁺ influx.
Membrane depolarization occurs.
Ca²⁺ influx and neurotransmitter release in the CNS, or fast post-synaptic excitation at the NMJ.
Q: What are the key functions of nAChRs?
A: They regulate skeletal muscle contraction, neuronal excitability, gene expression, learning & memory formation, and neuroprotection.
Q: What are the two subtypes of Nicotinic Acetylcholine Receptors (nAChRs)?
A:
Muscle (Nm) subtype – found at the neuromuscular junction (NMJ).
Neuronal (Nn) subtype – found in autonomic ganglia and the CNS.
Q: What is the structural composition of nAChRs?
A: They are pentameric complexes composed of five subunits.
Q: How many nAChR subunits have been identified, and how do they assemble?
A: 17 subunits cloned: α1–α10, β1–β4, γ, δ, and ε. They co-assemble into homo- or hetero-pentameric receptors.
Q: What subunit composition is typical for the muscle (Nm) subtype?
A: 2α1, β1, δ, and either γ or ε.
Q: What subunit composition is typical for the neuronal (Nn) subtype?
A:
Hetero-pentamers: 2α + 3β (e.g., α4β2).
Homo-pentamers: 5α7 (e.g., α7 homomeric receptors).
Q: What part of the muscle-type (Nm) nAChR forms the ion-conducting pore?
A: The M2 α-helices from all five subunits form and line the ion-conducting pore.
Q: How many acetylcholine (ACh) binding sites does the Nm nAChR have, and where are they located?
A: It has two ACh binding sites, located at the interface between the two α subunits and their neighboring δ & γ/ε subunits.
Q: What is required for Nm nAChR activation?
A: Both ACh binding sites must be occupied by ACh molecules for the receptor to activate.
Q: What is the role of the muscle (NM) subtype of nAChR in the autonomic nervous system (PNS)?
A: It occurs at the neuromuscular junction (NMJ) and mediates fast excitatory synaptic transmission, leading to skeletal muscle contraction.
Q: What is the role of the neuronal (NN) subtype of nAChR in the autonomic nervous system (PNS)?
A: It occurs post-synaptically at autonomic ganglia and mediates fast excitatory synaptic transmission, controlling autonomic functions of peripheral organs, such as the cardiovascular (CV) and gastrointestinal (GI) systems.
Q: What are the roles of the neuronal (NN) subtype of nAChR in the central nervous system (CNS)?
A: It occurs pre- and post-synaptically and plays key roles in:
Modulation of neurotransmitter release.
Neuronal excitability & integration.
Gene expression, differentiation & survival.
Cognition, learning & memory formation.
Neuroprotection.
Q: What activates GABA receptors?
A: GABA receptors are activated by the amino acid transmitter γ-aminobutyric acid (GABA).
Q: What happens when GABA binds to its receptor?
A: Binding of GABA leads to channel opening, allowing Cl⁻ influx, causing membrane hyperpolarization and resulting in fast post-synaptic inhibition.
Q: How is GABA receptor gating modulated?
A: GABA receptor gating is allosterically modulated by a variety of substances, including benzodiazepines, barbiturates, neurosteroids, anaesthetics (volatile & intravenous), and alcohol.
Q: Where are GABA receptors found, and what do they mediate?
A: GABA receptors are widely distributed in the CNS and mediate both fast (phasic) and tonic post-synaptic inhibition of neuronal activity.
Q: What is the role of GABA receptors in the CNS?
A: They mediate the actions of GABA as the main inhibitory neurotransmitter in the brain, as well as the effects of anxiolytic, antiepileptic, and general anaesthetic drugs.
Q: What is the structural composition of GABA receptors?
A: GABA receptors are pentamers composed of five subunits.
Q: How many subunit classes have been cloned for GABA receptors?
A: Eight subunit classes have been cloned: α1-6, β1-3, γ1-3, δ, ε, θ, π1-3.
Q: How do the subunits of GABA receptors assemble to form functional receptors?
A: The subunits co-assemble to form homo- or hetero-pentameric receptors. A common functional receptor is typically composed of two α-subunits, two β-subunits, and either a γ- or δ-subunit (e.g., 2α/2β/1γ or δ).
Q: How is the subunit composition of GABA receptors related to their location?
A: The subunit composition is related to whether the receptor is located synaptically or extrasynaptically.
Q: Where are the GABA binding sites located in the receptor?
A: The two GABA binding sites are located at the α/β subunit interfaces.
Q: Where are synaptic GABA receptors located and what do they mediate?
A: Synaptic GABA receptors are located post-synaptically at synaptic sites (within the synaptic cleft) and mediate phasic inhibition.
Q: What is the subunit composition of synaptic GABA receptors?
A: Synaptic GABA receptors typically contain a γ-subunit and α1, α2, or α3 subunits.
Q: How do synaptic GABA receptors respond to GABA and benzodiazepines?
A: They have lower affinity for GABA and high sensitivity to benzodiazepines.
Q: Where are extrasynaptic GABA receptors located and what do they mediate?
A: Extrasynaptic GABA receptors are located post-synaptically outside synaptic sites and mediate tonic inhibition.
Q: What is the subunit composition of extrasynaptic GABA receptors?
A: Extrasynaptic GABA receptors typically contain a δ-subunit and α4, α5, or α6 subunits.
Q: How do extrasynaptic GABA receptors respond to GABA and benzodiazepines?
A: They have higher affinity for GABA and low sensitivity to benzodiazepines.
Q: What substances preferentially modulate extrasynaptic GABA receptors?
A: Extrasynaptic GABA receptors are preferentially modulated by propofol, neurosteroids, and ethanol.
Q: Where are GABA receptors widely distributed in the brain?
A: GABA receptors have high densities in the cerebral cortex, hippocampus, and cerebellum.
Q: What are the main functional roles of GABA receptors in the CNS?
A:
They are the major inhibitory receptor in the CNS.
They mediate fast (phasic) and slow (tonic) neuronal inhibition.
Q: How are GABA receptors involved in physiological processes?
A: GABA receptors play a role in regulating feeding behavior, circadian rhythm, sleep-wake cycle, vigilance, learning, and memory.
Q: What is the role of GABA receptors in drug targeting?
A: GABA receptors are major targets for a wide range of therapeutic and recreational drugs, including benzodiazepines, barbiturates, neurosteroids, general anaesthetics, and alcohol.
Q: What disorders are GABA receptors implicated in?
A: GABA receptors are implicated in various disorders such as anxiety, sleep disorders, epilepsy, depression, mania, autism, psychosis, and alcoholism.
Q: How do drugs act on GABA receptors?
A: These drugs bind to specific allosteric binding sites on GABA receptors, enhancing or potentiating the effects of the endogenous agonist, GABA. This is known as positive allosteric modulation.
Q: What happens when a drug binds to the allosteric site of a GABA receptor?
A: Binding to the allosteric site causes a conformational change, which increases the receptor’s affinity for GABA, leading to greater GABA binding and channel opening, allowing Cl⁻ influx and membrane hyperpolarization, resulting in neuronal inhibition.
Q: What effect does allosteric modulation have on GABA receptor function?
A: It typically increases the frequency and/or duration of channel opening, leading to increased Cl⁻ influx and enhanced neuronal inhibition.
