ELM 1 Receptors 101 Flashcards
(134 cards)
1
Q
Q: What is a ligand?
A
A: A molecule that binds to a receptor.
2
Q
Q: What is an agonist?
A
A: A ligand that binds to a receptor and activates it.
3
Q
Q: What is an antagonist?
A
A: A ligand that binds to a receptor and prevents its activation, blocking the agonist binding site (competitive) or acting at a different site.
4
Q
Q: What is a subunit in the context of receptors?
A
A: A component protein of a receptor, with receptors made up of multiple subunits held together by non-covalent bonds.
5
Q
Q: Define monomer, dimer, trimer, tetramer, pentamer, and hexamer.
A
A: A monomer has 1 subunit, a dimer has 2 subunits, a trimer has 3 subunits, a tetramer has 4 subunits, a pentamer has 5 subunits, and a hexamer has 6 subunits.
6
Q
Q: What is a kinase?
A
A: An enzyme that phosphorylates its targets, regulating their activity by adding phosphate groups to amino acids with an OH group (tyrosine, serine, threonine).
7
Q
Q: What is an allosteric modulator?
A
A: A drug that binds to a site distinct from the agonist site and changes receptor behavior, which can be positive or negative.
8
Q
Q: What is the Greek letter for alpha, beta, gamma, delta, and epsilon?
A
A: α - alpha, β - beta, γ - gamma, δ - delta, ε - epsilon.
9
Q
Q: How do proteins and drugs interact in terms of size and binding?
A
A: Proteins are much larger (400,000 Da) compared to drugs (500 Da), so drugs contact only a small specific part of their target, the binding domain.
10
Q
Q: What types of bonds do most drugs form with their protein targets?
A
A: Most drugs form reversible bonds, which include hydrogen bonds, van der Waals forces, hydrophobic bonds, dipole-dipole interactions, dipole-ion interactions, and ionic bonds.
11
Q
Q: What is the significance of reversible vs. irreversible drug binding?
A
A: Reversible binding means the drug’s effect is temporary and allows for repeated dosing. Irreversible binding requires the body to synthesize new copies of the target protein for the effect to wear off.
12
Q
Q: Name three drugs that form covalent bonds with their targets.
A
A: Aspirin, clopidogrel, and omeprazole.
13
Q
Q: What is a receptor in pharmacology?
A
A: A protein that binds a molecular message and passes the information contained in that message on in a different form (signal transduction).
14
Q
Q: What percentage of drug targets are receptors, and which type is most common?
A
A: 40-60% of drug targets are receptors, with more than half being G protein-coupled receptors.
15
Q
Q: What is a superfamily in the context of proteins?
A
A: A broad grouping of proteins related to each other in structure and function.
16
Q
Q: What is the organizational hierarchy within a protein superfamily?
A
A: Superfamily, family, subfamily.
17
Q
Q: What is an example of a protein superfamily?
A
A: G protein-coupled receptors (GPCRs).
18
Q
Q: How many members are there in the GPCR superfamily, and how are they categorized?
A
A: Over 800 members, divided into 6 families based on amino acid sequence and functional similarities.
19
Q
Q: What is the largest family within the GPCR superfamily?
A
A: The Rhodopsin-like family (Family A) with over 600 members.
20
Q
Q: How many subfamilies are in the Rhodopsin-like family?
A
A: 19 subfamilies.
21
Q
Q: What is an example of receptors in Family A with multiple subtypes?
A
A: Muscarinic acetylcholine receptors, with 5 different types each coded by a separate gene.
22
Q
Q: How do protein superfamilies arise?
A
A: From a single ancestral protein through gene duplication and subsequent mutation.
23
Q
Q: What happens during gene duplication?
A
A: An organism gets a redundant copy of an essential gene, allowing one copy to acquire mutations and potentially gain a new function.
24
Q
Q: What are the evolutionary advantages of protein diversity?
A
A: Greater flexibility and adaptability to the environment, and the potential for new functions and interactions.
25
Q: How can the diversity of receptors aid drug development?
A: By targeting specific receptor subtypes to treat different conditions more effectively.
26
Q: How many types of adrenoceptors are there, and how are they classified?
A: Nine types, classified into alpha (α) and beta (β) subtypes.
27
Q: What is the role of the β1 adrenoceptor, and how can it be targeted in drug development?
A: Heavily expressed in the heart, increases heart rate and force of contraction. Blocking β1 without affecting β2 is useful for treating angina (e.g., atenolol).
28
Q: What is the role of the β2 adrenoceptor, and how can it be targeted in drug development?
A: Expressed in bronchial smooth muscle, causes airway dilation. Activating β2 without affecting β1 is useful for treating asthma (e.g., salbutamol).
29
Q: Why is receptor diversity vital for drug development?
A: It allows for the creation of drugs that can specifically target different receptor subtypes for precise therapeutic effects.
30
Q: What are ligand-gated ion channels (LGICs)?
A: Transmembrane proteins with built-in ion channels that open in response to the binding of a neurotransmitter ligand, allowing ions to cross the membrane and change cell behavior.
31
Q: How many agonist binding sites do most ligand-gated ion channels have, and what is required for channel opening?
A: Most have 2 binding sites for agonists, and both must be occupied for the ion channel to open.
32
Q: What is selective permeability in the context of LGICs?
A: The property that allows only specific types of ions to pass through the ion channel based on the concentration gradient.
33
Q: What happens to an LGIC when the agonist dissociates?
A: The receptor returns to its inactive state, and the ion channel closes.
34
Q: What is the general structure of pentameric LGICs?
A: They consist of 5 subunits arranged in a ring around an integral ion channel, with each subunit having 4 transmembrane domains and a large N-terminal extracellular domain for agonist binding.
35
Q: How many transmembrane domains do the subunits of pentameric LGICs have?
A: Four transmembrane domains.
36
Q: What forms part of the ion channel lining in pentameric LGICs?
A: The second transmembrane domain of each subunit.
37
Q: In which kingdoms of life are pentameric LGICs found?
A: They are present in all three kingdoms of life (Archaea, Bacteria, and Eukarya).
38
Q: Describe the role of the N-terminal extracellular domain in pentameric LGICs.
A: It contributes to the agonist binding sites.
39
Q: What determines the direction of ion movement through an LGIC?
A: The concentration gradient of the ions.
40
Q: What type of channels are nAChRs?
A: Cation channels permeable to Na+, K+, and Ca2+.
41
Q: What occurs when nAChRs are activated?
A: Na+ and Ca2+ enter the cell, depolarizing the membrane and producing excitatory effects.
42
Q: What is the natural agonist of nAChRs, and what else can activate them?
A: The natural agonist is acetylcholine (ACh), and they can also be activated by nicotine.
43
Q: What is the physiological importance of nAChRs?
A: They are responsible for fast excitatory transmission between motor neurons and skeletal muscle and also play a role in autonomic ganglia and neurotransmitter modulation in the CNS.
44
Q: Why are nAChRs important pharmacologically in skeletal muscles?
A: They are targets of drugs used to block neuromuscular transmission to relax muscles during surgery.
45
Q: Why are brain nAChRs significant in pharmacology?
A: They are the targets of nicotine and drugs that treat addiction.
46
Q: How were nAChRs first identified?
A: They were identified in skeletal muscle due to the availability of large amounts and the presence of several snake toxins that target these receptors.
47
Q: How many subunits are in the nAChR family, and how do they form receptors?
A: There are 16 subunits that come together in different combinations to form various receptor subtypes.
48
Q: What are the five different classes of nAChR subunits?
A: α (alpha), β (beta), γ (gamma), δ (delta), and ε (epsilon).
49
Q: How many different alpha and beta subunits exist in humans?
A: Nine alpha subunits (α1-7, α9, α10) and four beta subunits (β1-4).
50
Q: What are the three most important classes of nAChRs based on location?
A: Skeletal muscle, autonomic ganglia, and CNS (main target of nicotine).
51
Q: What role does nAChRs' ability to regulate dopamine play in nicotine addiction?
A: It makes nicotine highly addictive by modulating the release of dopamine in the CNS.
52
Q: What type of channels are GABA A receptors?
A: Chloride channels that, when activated, allow chloride ions to enter the cell.
53
Q: What effect does the activation of GABA A receptors have on a cell?
A: Hyperpolarizes the cell, making it less excitable.
54
Q: What is the natural agonist of GABA A receptors?
A: GABA (gamma-aminobutyric acid), an amino acid.
55
Q: What is another compound that activates GABA A receptors?
A: Muscimol, the main psychoactive compound from fly agaric mushrooms.
56
Q: What is the physiological importance of GABA A receptors?
A: GABA is the main inhibitory neurotransmitter in the brain, with 20% of neurons producing it and 30% of synapses in the CNS using it.
57
Q: How do GABA A and GABA B receptors differ?
A: GABA A receptors are ion channels that produce fast synaptic inhibition, while GABA B receptors are GPCRs that produce slower inhibition.
58
Q: What is the pharmacological importance of GABA A receptors?
A: They are targets for many drugs that dampen brain activity by potentiating the effects of GABA and are termed positive allosteric modulators.
59
Q: What happens if GABA is inhibited?
A: It can lead to anxiety and an increased risk of seizures.
60
Q: How many subunits compose GABA A receptors, and how are they structured?
A: There are 19 different subunits that form pentameric receptors in various combinations, leading to a few dozen receptor types.
61
Q: What are some of the GABA A receptor subunit types?
A: α (alpha) 1−6, β (beta) 1−3, γ (gamma) 1−3, δ (delta), ε (epsilon), π (pi), θ (theta), and ρ (rho) 1−3.
62
Q: What type of channels are ionotropic glutamate receptors (iGluRs)?
A: Cation channels.
63
Q: What are the three families of iGluRs, and what are they named after?
A: NMDA, AMPA, and kainate receptors, named after drugs that are selective agonists.
64
Q: What are the natural agonists of iGluRs?
A: The excitatory amino acid neurotransmitters glutamate and aspartate.
65
Q: What is the physiological importance of glutamate receptors?
A: Glutamate is the primary excitatory neurotransmitter in the CNS, with fast transmission by iGluRs and slower transmission by metabotropic GluRs (GPCRs).
66
Q: What is the significance of NMDA receptors being highly permeable to calcium?
A: They are important in learning and memory due to their calcium permeability.
67
Q: What is the pharmacological importance of inhibiting NMDA receptors?
A: NMDA inhibition is part of the mechanism of many anesthetics, such as ketamine and nitrous oxide, and Alzheimer's drug memantine acts at these receptors.
68
Q: What can excessive activation of iGluRs lead to?
A: Excitotoxic brain damage, which is a potential pathological mechanism for neurodegenerative diseases caused by certain dietary toxins.
69
Q: How are iGluRs structured?
A: They are tetramers with a membrane topology different from pLGICs.
70
Q: What is the structure of receptor tyrosine kinases (RTKs)?
A: RTKs are large proteins with a single transmembrane domain and an intracellular tyrosine kinase domain. They may exist as monomers or dimers.
71
Q: What is the primary function of the tyrosine kinase domain in RTKs?
A: The tyrosine kinase domain phosphorylates tyrosine residues on target proteins.
72
Q: What happens during the agonist binding step in RTK activation?
A: The RTK dimerizes, and the receptor’s tyrosine kinase domain becomes activated. In some RTKs, this step is necessary even if they preexist as dimers.
73
Q: What occurs during the autophosphorylation step of RTK activation?
A: The RTK phosphorylates tyrosine residues on its partner RTK.
74
Q: What role do adapter proteins play in RTK signaling?
A: Activated RTKs bind and phosphorylate intracellular adapter proteins, linking the RTK to intracellular signaling pathways.
75
Q: How many RTKs are there in the human genome, and what roles do they play?
A: There are 58 RTKs in the human genome, and they bind various peptide signaling molecules involved in growth and metabolism.
76
Q: Name a member of the RTK family and its significance.
A: The insulin receptor is a member of the RTK family, and HER2 is another member important in regulating epithelial cell division and differentiation, especially relevant in breast cancer therapeutics.
77
Q: What are some pharmacological applications of RTK-targeting drugs?
A: Drugs like insulin, herceptin (targets HER2), and gleevec (inhibits several RTKs) are used in diabetes management and cancer treatment.
78
Q: How many nuclear receptors are in the human genome, and what are "orphan" receptors?
A: There are 48 nuclear receptors in the human genome, and 10 of them are "orphan" receptors, meaning they do not have an identified natural ligand.
79
Q: What is the mechanism of action for nuclear receptors?
A: Nuclear receptors bind lipophilic agonists, dissociate from companion proteins, dimerize, move to the nucleus, bind to hormone response elements, and alter transcription rates of target genes.
80
Q: What physiological functions do nuclear receptors regulate?
A: Nuclear receptors regulate basic functions such as glucose metabolism, inflammation, immune response, salt and water balance, blood pressure, metabolism, and development.
81
Q: Which hormones act through nuclear receptors?
A: Steroid sex hormones, cortisol, aldosterone, and thyroxine act through nuclear receptors.
82
Q: What is the role of glucocorticoid receptors?
A: Glucocorticoid receptors regulate glucose metabolism and inflammation, with cortisol as the main agonist.
83
Q: What happens when there is too little or too much cortisol?
A: Too little or too much cortisol can lead to illness due to dysregulation of glucose metabolism and the immune system.
84
Q: What is the function of mineralocorticoid receptors?
A: Mineralocorticoid receptors regulate salt and water balance, and control blood pressure, with aldosterone as the main agonist.
85
Q: How does aldosterone imbalance affect health?
A: Too much aldosterone can cause fatigue, potassium loss, high blood pressure, and cardiovascular conditions.
86
Q: What is the significance of thyroid hormone receptors?
A: Thyroid hormone receptors regulate metabolism and development, modulating heart rate and various physiological processes.
87
Q: What are the consequences of thyroid hormone imbalance?
A: Excess thyroxine can cause rapid heart rate, tremor, weight loss, and muscle weakness, while deficiency can lead to depression and developmental impairments.
88
Q: What is a common treatment for hyperthyroidism?
A: Hyperthyroidism is often treated by destroying the thyroid gland, followed by lifelong supplementation with synthetic thyroid hormone (thyroxine tablets).
89
Q: What structural components do all nuclear receptors share?
A: All nuclear receptors have a DNA-binding domain linked to a ligand-binding domain (LBD) by a hinge region, where the agonist binds.
90
Q: What do GPCRs link together in cell signaling?
A: GPCRs link an extracellular signal to intracellular signaling pathways using an accessory protein, the G protein.
91
Q: How many different alpha, beta, and gamma subunits do humans have for G proteins?
A: Humans have 18 different alpha subunits, 5 beta subunits, and 12 gamma subunits.
92
Q: Into how many main classes can G proteins be grouped?
A: G proteins can be grouped into 4 main classes: Gs, Gi/o, Gq, and G12.
93
Q: What are the components of trimeric G proteins?
A: Trimeric G proteins consist of alpha, beta, and gamma subunits.
94
Q: What feature allows the alpha subunit of a G protein to hydrolyze GTP to GDP?
A: The alpha subunit has a built-in GTPase.
95
Q: How are G protein subunits anchored to the membrane?
A: Lipid tails are added to G protein subunits after translation to anchor them to the membrane.
96
Q: Where is the agonist binding pocket located on GPCRs?
A: The binding pocket is located on the extracellular face of the receptor.
97
Q: What happens when an agonist binds to a GPCR?
A: The receptor activates, allowing it to interact with the G protein, causing the G protein's alpha subunit to swap GDP for GTP, thus activating the G protein.
98
Q: How does the alpha subunit of a G protein activate target proteins?
A: The alpha subunit dissociates from the beta and gamma subunits, diffuses along the membrane, and interacts with target proteins, often enzymes that produce second messengers.
99
Q: What is the role of the beta-gamma complex in GPCR signaling?
A: The beta-gamma complex can also modify the activity of membrane proteins, such as ion channels.
100
Q: How is GPCR signaling terminated?
A: Signaling is terminated when the agonist dissociates from the receptor, and the alpha subunit hydrolyzes GTP to GDP, then reassembles with the beta and gamma subunits.
101
Q: What common structural feature do all GPCRs share?
A: All GPCRs have a serpentine structure, with seven transmembrane (7TM) alpha-helical regions.
102
Q: Where are the agonist and G protein binding sites located on GPCRs?
A: The agonist binding site is in the upper center of the receptor, and the G protein binding site is formed by amino acids in specific regions of the receptor.
103
Q: Why is the specificity of GPCR and G protein binding important?
A: Specificity allows cells to respond to different extracellular signaling molecules by specifically activating different intracellular signaling pathways.
104
Q: What is the second messenger molecule involved in GPCR signaling with Gs and Gi/o proteins?
A: The second messenger molecule is cyclic AMP (cAMP).
105
Q: How is cAMP produced and degraded in the cell?
A: cAMP is produced from ATP by adenylyl cyclase and degraded by phosphodiesterase (PDE) to yield AMP.
106
Q: What is the primary mechanism by which cAMP changes cell function?
A: The primary mechanism is through the activation of protein kinase A (PKA).
107
Q: How is PKA activated by cAMP?
A: PKA is activated when its regulatory subunits bind to cAMP, releasing the catalytic subunits which then become active.
108
Q: What types of residues does PKA phosphorylate on target proteins?
A: PKA phosphorylates serine and threonine residues on target proteins.
109
Q: How does cAMP regulate HCN channels in the heart?
A: cAMP binds to HCN channels, modulating their activity, which is important for pacemaker currents generated in the sinoatrial node.
110
Q: What does the "s" in Gs stand for, and what is its effect on adenylyl cyclase?
A: The "s" in Gs stands for stimulation, as it stimulates the activity of adenylyl cyclase, increasing the concentration of cAMP.
111
Q: What happens when an agonist binds to a GPCR in the Gs pathway?
A: The GPCR activates and interacts with a G protein, causing GDP to be replaced by GTP, activating the G protein.
112
Q: How does the alpha subunit of the G protein affect adenylyl cyclase in the Gs pathway?
A: The alpha subunit dissociates from the beta-gamma subunits and binds to adenylyl cyclase, stimulating it to increase cAMP production.
113
Q: How is the signaling via Gs terminated?
A: The alpha subunit hydrolyzes GTP to GDP and reassociates with the beta-gamma subunits, adenylyl cyclase is no longer stimulated, and cAMP levels return to basal levels as the agonist dissociates from the receptor.
114
Q: What is the main effect of signaling via Gi/o on adenylyl cyclase?
A: Signaling via Gi/o decreases the activity of adenylyl cyclase, reducing the concentration of cAMP.
115
Q: How do the beta-gamma subunits of Gi/o proteins affect target proteins?
A: The beta-gamma subunits modulate some membrane proteins directly.
116
Q: What happens to the alpha subunit of Gi/o when an agonist binds to a GPCR?
A: The alpha subunit dissociates from the beta-gamma subunits and binds to adenylyl cyclase, inhibiting it and decreasing cAMP levels.
117
Q: How is signaling via Gi/o terminated?
A: The alpha subunit hydrolyzes GTP to GDP and reassociates with the beta-gamma subunits, adenylyl cyclase is no longer inhibited, and cAMP levels return to basal levels as the agonist dissociates from the receptor.
118
Q: What second messengers are involved in Gq signaling?
A: Diacylglycerol (DAG) and inositol trisphosphate (IP3).
119
Q: What is PIP2 and how is it involved in Gq signaling?
A: PIP2 is a membrane lipid that is cleaved by phospholipase C (PLC) to yield DAG and IP3.
120
Q: What roles do DAG and IP3 play in Gq signaling?
A: DAG remains in the membrane and modulates membrane proteins, while IP3 is released into the cytoplasm and modulates proteins in the endoplasmic reticulum (ER), leading to an increase in intracellular Ca2+ concentration.
121
Q: How does the alpha subunit of Gq activate PLC?
A: The alpha subunit dissociates from the beta-gamma subunits and binds to PLC, stimulating it to cleave PIP2, resulting in increased levels of DAG and IP3.
122
Q: What is the main effect of IP3 in the cell?
A: IP3 releases Ca2+ from the ER by binding to a Ca2+ channel, which can then activate other Ca2+ channels like the ryanodine receptor, causing Ca2+-induced Ca2+ release.
123
Q: How is Ca2+ signaling terminated in the cell?
A: Ca2+ pumps in the ER constantly pump Ca2+ back into stores, quickly returning cytoplasmic Ca2+ concentrations to basal levels once the GPCR signal is turned off.
124
Q: How can the beta-gamma complex activate PLC?
A: Several types of PLC can be activated by G protein beta-gamma complexes, not just the alpha subunit of Gq.
125
Q: Why is it important for cells to maintain low cytoplasmic Ca2+ concentrations?
A: Ca2+ regulates many cellular processes, so its concentration must be tightly controlled to prevent unwanted activation of these processes.
126
Q: What process is known as Ca2+-induced Ca2+ release?
A: The process where IP3-induced release of Ca2+ from the ER activates additional Ca2+ channels like the ryanodine receptor, leading to further Ca2+ release.
127
Q: How does Ca2+ modulate the activity of various proteins?
A: Ca2+ binds directly to many proteins, ion channels, and enzymes, modulating their activity.
128
Q: What role does Ca2+ play in muscle contraction?
A: In muscle contraction, Ca2+ binds to troponin, initiating the interaction between actin and myosin.
129
Q: How does Ca2+ regulate contraction in smooth muscle?
A: In smooth muscle, Ca2+ binds to calmodulin, which then regulates contraction.
130
Q: What is the role of calmodulin in Ca2+ signaling?
A: Calmodulin mediates many of the regulatory functions of Ca2+ by binding to it and altering the activity of target proteins.
131
Q: What type of protein is Protein Kinase C (PKC)?
A: PKC is a cytosolic protein that associates with the membrane upon binding to Ca2+.
132
Q: How does PKC become active?
A: PKC becomes active when it binds both Ca2+ and diacylglycerol (DAG), which are produced by the activation of Gq.
133
Q: What residues does PKC phosphorylate on target proteins?
A: PKC phosphorylates serine and threonine residues on target proteins.
134
Q: What is the importance of PKC in cellular regulation?
A: PKC is a key player in the regulation of cell processes across a diverse range of tissues, as it phosphorylates a wide range of proteins.
