Receptors 101 Flashcards

Question

What is an antagonist?

Answer 1

A ligand that binds to the receptor and stops it from activating May block the binding site or acts in a different site

Answer 2

Diaglycerol A second messenger that along with calcium, activates protein kinase C

Answer 3

A molecular switch that transduces signals from G protein coupled receptors to intracellular signalling pathways

Answer 4

A superfamily of ligand gated ion channels that mediate fast synaptic transmission in the central nervous system by binding glutamate

Answer 5

An enzyme that transfers phosphate groups from high energy molecules (such as ATP) to specific substrates in a process called phosphorylation

Answer 6

- aspirin - clopidogrel - omeprazole

Answer 7

Through gene duplication and subsequent mutations Mutations may be harmful or fatal if the protein is essential for cell function

Answer 8

Flexibility - Independent regulation —> allows them to be turned on/off at different stages of development and expressed at different levels in tissues due to multiple genes coding for slightly different versions of a receptor - Respond to new signals —> due to having ‘spare’ receptors that get mutated which changes the agonist binding site so it recognises different signalling molecules

Answer 9

Has 2 binding sites for the agonist and both must be occupied to activate the receptor

Answer 10

- 5 subunit - ancient superfamily - also known as cys loop receptors & nicotinoid receptors - each subunit has 4 TM domains, large extracellular N terminus (agonist binding site), arranged around a central ion channel and the 2nd TM from each subunit forms part of the ion channel lining

Answer 11

Can be homopentamers (6 identical subunits) or heteropentamers (different types of subunits) - agonist binding sites on the N-terminal (outside cell) fold together with the N terminal domains of neighbouring subunits to form binding sites - 4 transmembrane domains where all pLGIC receptor subunits pass through the membrane 4 times - regulatory sites which regulate the receptor function and this is the part where the receptor is tethered to the cytoskeleton - channel lining is the TM2 domain which contains hydrophilic amino acids that come together to form a pathway through the membrane for the ions - channel lumen at the centre of TM2 domain —> diameter increases when channel activates = what ‘gates’ the channel

Answer 12

- large family of pLGICs - all cation channels permeable to Na+, K+ and Ca2+ - bring about excitatory effects - natural agonist is ACh - tobacco toxin nicotine is also an agonist

Answer 13

- Block of skeletal muscle nACh receptors during surgery = relax muscle - Targets of nicotine = used to treat addiction - Model receptor = first ligand gated receptor to be characterised in a lab & easy to obtain in large quantities

Answer 14

Consists of 16 different subunits 5 classes of subunits - alpha 1-7,9,10 - beta 1-4 - other class as one subtype 3 classes of receptors - adult skeletal muscle - autonomic ganglia - brain nicotine binding site

Answer 15

Target a huge range of drugs - general anaesthetics - anti-epilepsy medication - ant-anxiety drugs (e.g. diazepam) - alcohol All are positive allosteric modulators —> make the receptor work better by binding to a site other than the GABA binding site

Answer 16

- γ-aminobutyric acid type A receptor = all chloride channels - Chloride channels = produce synaptic inhibition —> when activated, allow more Cl- entry into the cell and hyperpolarises the cell (less excitable) - Target of muscimol = main psychoactive compound from fly agaric mushrooms which can activate GABA A receptors

Answer 17

- 19 different subunits - α1−6, β1−3, γ1−3, δ, ε, π (pi), θ (theta) and ρ1−3 (rho) - NOT the same proteins as nAChR subunits

Answer 18

GABA-A pLGIC = fast synaptic transmission GABA-B = G-coupled receptors producing slower inhibition

Answer 19

- different superfamily to pLGIC - 3 subtypes - cation channels - NMDA and some AMPA receptors are calcium permeable - Natural agonists are glutamate and aspartate

Answer 20

- Glutamate is the main excitatory transmitter in the CNS - Also have metabotropic glutamate receptors (mGluR) which are GPCRs = slower responses - NMDA receptors partially important in learning and memory = more calcium permeable

Answer 21

- Target of many general anaesthetics e.g. ketamine & nitrous oxide - Target of Alzheimer’s drug memantine = acts as NMDA receptors - Important in excitotoxicity where certain dietary toxins can cause Neurodegenerative diseases

Answer 22

- Tetramers that can be homometric but some (NMDA) are always heterometric - 4 agonist binding sites (one per subunit) - Agonist binding sites are in the N-terminal domains of the subunits - Have 3 TM domains with the N terminus extracellular and the C terminus intracellular - Channel forming segment is between the first and second TM domains, it enters the membrane from the cytoplasmic side then loops back in the cytoplasm without fully crossing the membrane

Answer 23

All are transmembrane receptors for peptide signalling molecules Not a single superfamily = compromised of several superfamilies that share a common mechanism Common mechanism = recruit an enzyme when activated —> can be integral (part of receptor) or separate (cytoplasmic protein that binds to an activated receptor)

Answer 24

- Large, single TM domain - Can be monomers or dimers (e.g. insulin) - Intracellular tyrosine kinase domain = phosphorylates tyrosine residues (alters structure) & modifies behaviour of target protein

Answer 25

- RTK located in the cell membrane - Signal molecule binding and receptor dimerisation activates RTK domains - Some RTKs pre-exist in the membrane in dimeric form which is still necessary for tyrosine kinase domain to be activated - But in some RTKs, the ligand is dimeric and bridges between 2 receptors to bring them together - Tyrosine kinase domains on each RTK phosphorylates tyrosine on their partner RTK - Results in activated intracellular adapter proteins - The activated receptor now binds intracellular adapter proteins and activates them by phosphorylating tyrosine residues - The adaptor proteins link RTK to intracellular signalling pathways

Answer 26

- 58 in the human genome - Bind peptide signalling molecules = roles in regulating growth & metabolism Such as - insulin receptors —> best known receptor in this superfamily - HER2 receptor —> regulates epithelial cell division and differentiation (important in breast cancer therapeutics)

Answer 27

Targets of - insulin - herceptin = monoclonal antibody that targets HER2 - gleevec (imatinib) = inhibits several different RTKs & has applications in a range of cancers & leukaemias

Answer 28

- bind lipophilic signals which can dissolve in the membrane and enter the cytoplasm - located inside the cell rather than in the cell membrane - 48 in the human genome —> 10 are orphan receptors - diverse range of ligands = sex steroids to vitamin D

Answer 29

In order from left to right - N-terminal domain - DNA binding domain (DBD) - Hinge region = links DBD & LDB - Ligand binding domain (LBD) = where agonist binds - C-terminal domain

Answer 30

**Glucocorticoid receptors** - Glucose metabolism - Inflammation/immune function —> if the body produces too much cortisol, results in serious illness and if there is not enough cortisol, results in serious illness and possible death - Main natural ligand is cortisol —> synthesised in the adrenal cortex **Mineralocorticoid receptors** - Salt and water balance —> important in blood pressure control - Main natural ligand is aldosterone —> synthesised in the adrenal cortex and excessive production results in fatigue, high blood pressure and K+ loss = cardiovascular conditions e.g. stroke **Thyroid hormone receptors** - Metabolism - Development - Heart rate - Main natural ligand is thyroid hormone (T3) & Thyroxine (T4) is a prohormone for T3 —> too much thyroid hormone results in rapid HR, tremors, weight loss, muscle weakness and too little thyroid hormone results in slow HR, weight gain, fatigue, depression which if occurs in early development, causes intellectual disability & physical impairments

Answer 31

Steroid sex hormone receptors - oral contraceptives; tamoxifen (breast cancer) & androgens (sports) - increase muscle mass to enhance sport performance Glucocorticoid receptors - anti-inflammatory drugs; prednisolone & dexamethasone - latter used to treat asthma or other autoimmune conditions Mineralocorticoid receptors - spironolactone (aldosterone agonist) - important target in cardiovascular conditions such as hypertension Thyroid hormone receptors - synthetic thyroid hormone for hypothyroidism and hyperthyroidism - typically treated by destroying parts or all of the thyroid gland so synthetic thyroid ensures they have correct plasma concentrations of the hormone

Answer 32

Trimeric membrane-associated proteins - Lipid tails added in post-translational modifications of the subunits anchor the G protein subunits to the membrane - Beta/gamma complex = subunits are tightly bound together and work as a single entity - Alpha subunit = has a built in GTPase enzyme & can dissociate and operate on its own - GDP = bound to Alpha subunit and is exchanged for GTP when the alpha subunit is activated

Answer 33

1. Agonist binding —> an extracellular signal (hormone or neurotransmitter) binds to the GPCR which has the binding pocket on the extracellular face of the receptor 2. Receptor activation, binding to G protein —> activation via agonist binding allows the receptor to interact with the G protein and the alpha subunit then swaps GDP for GTP which activates the G protein 3. Signal amplification —> once the GPCR has activated the G protein, it is free to diffuse through the membrane and activate more G proteins = results in initial signal being amplified 4. Alpha subunit interacts with target protein —> alpha subunit dissociates from beta/gamma complex and diffuses along the membrane then interacts with the target protein (secondary messenger) & changes its activity. Effects of the secondary messenger brings about changes in cell activity 5. Beta gamma signalling —> in some circumstances, beta/gamma complex can modify the activity of membrane proteins such as ion channels

Answer 34

1. Agonist dissociation —> signal is terminated by the initial agonist signal dissociating from the receptor and rebinding is prevented by the reuptake of the agonist into surrounding cells or breakdown by enzymes (this occurs randomly) 2. G-protein deactivation —> inside the cell, the signalling system is shut down by the alpha subunit hydrolysing GTP to GDP and P so the G protein is no longer active and the alpha subunit reassembles with beta/gamma complex 3. Cycle completes —> back at the starting configuration where GDP is bound to the G protein and the receptor is in a resting state

Answer 35

- linked to Gs and Gi - produced from ATP by membrane enzyme adenylyl cyclase - depends on activity of phosphodiesterases (PDE) as well as adenylyl cyclase - PDE enzymes break down cAMP to yield AMP - PDE enzymes are drug targets e.g. caffeine increases [cAMP] by blocking cAMP breakdown by PDE

Answer 36

- found in the cytoplasm as an inactive tetramer - consists of 2x regulatory subunits and 2x catalytic subunits - when regulatory subunits each bind 2 molecules of cAMP, the catalytic subunits are released and become active - PKA phosphorylates Ser & Thr which results in changes in protein activity - has a wide range of targets and is present in many tissues

Answer 37

- can modulate some proteins directly - e.g. HCN channels in the heart = important in the cardiac pacemaker cells in the SA node

Answer 38

Stimulates activity of adenylyl cyclase and thus increases intracellular [cAMP] 1. Agonist binds to GPCR and activates it 2. The active GPCR diffuses through the membrane and interacts with Gs 3. GDP is replaced by GTP and the G protein activates 4. Active G protein splits into beta/gamma complex and an alpha subunit with GTP attached. The active receptor is free to activate further G proteins 5. Active alpha s subunit stimulates an increased rate of cAMP production so intracellular cAMP concentration rises 6. The alpha s subunit hydrolyses GTP and dissociates from adenylyl cyclase and reassociates with beta/gamma. Intracellular cAMP concentration returns back to basal levels as adenylyl cyclase is no longer stimulated 7. Agonist dissociates from the receptor which deactivates & the cycle is complete

Answer 39

- Beta adrenergic receptors (adrenoreceptors) —> treats acute asthma attacks where salbutamol is the agonist - Adrenocorticotropic hormone (ACTH) receptors - Corticotropin-releasing hormone (CRH) receptors - Adenosine receptors A2A

Answer 40

Decreases the activity of adenylyl cyclase and thus decreases intracellular [cAMP] BY-subunit modulates some proteins directly 1. Agonist binds to GPCR and activates it 2. The active GPCR diffuses through the membrane and interacts with Gi (G protein) 3. G protein GDP is replaced by GTP and the G protein activates 4. Active G protein splits into beta/gamma complex and an alpha subunit with GTP attached. The active receptor is free to activate further G proteins 5. The active alpha i subunit inhibits adenylyl cyclase and so enzymes rate of cAMP production decreases and intracellular cAMP concentration goes down 6. Alpha i subunit hydrolyses GTP to GDP + Pi and then dissociates from adenylyl cyclase & reassociates with beta/gamma. Intracellular [cAMP] returns to basal levels as adenylyl cyclase is no longer inhibited 7. Agonist dissociates from the receptor which deactivates

Answer 41

- Muscarinic acetylcholine receptors M2 and M4 subtypes - alpha2 adrenergic receptors - Adenosine A1 and A3 receptors

Answer 42

- Involves the membrane enzyme phospholipase C which cleaves membrane lipids resulting in the direct formation of 2 different secondary messenger molecules and an indirect increase in the cytosolic concentration of a third secondary messenger molecule - Couples to intracellular pathways via 2 secondary messengers —> IP3 (increases intracellular Ca2+) and DAG - Phospholipase C cleaves PIP2 which has 3 important components —> 2 fatty acid tails and a phosphoinositol head group which form DAG & a glycerol linker

Answer 43

1. Agonist binds to G protein coupled receptor & activates it 2. The active G protein coupled receptor with agonist attached diffuses through the membrane and interacts with the Gq G protein 3. G protein GDP is replaced by GTP and the G protein activates 4. Active G protein splits into beta gamma complex & an alpha subunit with GTP attached. The active receptor is free to activate further G proteins. 5. The active alpha q subunit binds to phospholipase C 6. Alpha q with GTP bound activates phospholipase C (PLC) & PLC cleaves to PIP2 to yield DAG (modulates membrane proteins) and IP3 (modulates proteins in the ER). This increases the concentration of DAG in the membrane and IP3 in the cytoplasm. 7. Alpha q subunit hydrolyses GTP to GDP + P. It dissociates from phospholipase C and reassociates with beta gamma = phospholipase C is no longer stimulated 8. Agonist dissociates from receptor which deactivates. Cycle is complete

Answer 44

Releases Ca2+ from the ER which can then activate another calcium channel 1. Cleavage of PIP2 —> PLC cleaves the membrane lipid PIP2 to yield DAG & IP3. The IP3 is released into the cytoplasm 2. Activation of IP3 receptor —> IP3 binds to the IP3 receptor on the ER (or the Sarcoplasmic reticulum in muscles) 3. Release of Ca2+ from the ER —> IP3 receptor is a calcium channel and when open, Ca2+ flows down a concentration gradient from the ER into the cytoplasm 4. Activation of the ryanodine receptor —> activated by the increase in cytoplasmic Ca2+ so calcium floods out of the ER through the ryanodine receptor and into the cytoplasm

Answer 45

- M1, M3 and M5 muscarinic acetylcholine receptors (regulate smooth muscle contraction via ANS) - Alpha1 adrenergic receptors

Receptors 101 Flashcards

(69 cards)