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Drugs: from molecules to man > Drug targets 2 > Flashcards

Drug targets 2 Flashcards

1
Q

What percentage of drugs target ion channels?

A

About 11%

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2
Q

What are drugs targeting ion channels important in treating?

A

Cardiovascular disorders

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3
Q

Why can’t ions penetrate lipid bilayers?

A

They are charged

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4
Q

How does an ion channel help ions move through?

A

the channel is lined with amino acids that interact positively with the ion

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5
Q

What mechanism do ion channels work through?

A

Diffusion

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6
Q

What are the basic properties of all ion channels?

A
  • All ion channels are transmembrane proteins
  • All selectively permeable
  • Opening and closing are controlled (gating)
  • Diverse
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7
Q

What is the sodium gradient of a mammalian cell and what happens when the channel opens?

A
  • Inside: 15mM
  • Outside: 150mM
  • Sodium moves from outside to inside – depolarisation (membrane becomes more positive)
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8
Q

What is the potassium gradient of a mammalian cell and what happens when the channel opens?

A
  • Inside: 100mM
  • Outside: 5mM
  • Hyperpolarization (membrane becomes more negative) – K+ moves from inside to outside
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9
Q

What is the chlorine gradient of a mammalian cell and what happens when the channel opens?

A
  • Inside: 13mM
  • Outside: 150mM
  • Hyperpolarisation – outside to inside
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10
Q

What is the calcium gradient of a mammalian cell and what happens when the channel opens?

A
  • Inside: 0.002mM
  • Outside: 2mM
  • Outside to inside – diverse outcome as it is a signalling molecule
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11
Q

What are the different types of gating?

A 
 Mechanical 
 Second messenger inhibitory/activating 
 Phosphorylation 
 Leak (open most of the time) 
 Ligand-gated
 Voltage-gated
 Proton-gated
 G-protein-gated
 Temperature-gated
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12
Q

What are ion channels classified by?

A

 Gating
 Ion selectivity
 E.g. voltage-gated potassium channel

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13
Q

How are ligand-gated channels named?

A

named after natural ligand (activating molecule), e.g. GABAA receptor – chloride channel whose opening and closing is controlled by Gabba-aminobutyric acid – a neurotransmitter. When two molecules of GABA bind to the receptor the chloride channel opens

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14
Q

What is the basic working of voltage gated ion channels?

A

Channels are normally in a closed state, membrane potential changes (usually depolarisation), channel opens, ion is able to cross the membrane

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15
Q

What are the different types of voltage-gated ion channels?

A
  • Calcium channels (Cav)
  • Sodium channels (Nav)
  • Potassium channels (Kv)
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16
Q

What is the structure of the potassium channel?

A
  • Tetramer of four equivalent subunits
  • Crosses the membrane 6 times fully – 6 transmembrane domains (TM domain)
  • Membrane dipping domain between 5th and 6th domain (dips but doesn’t go all the way through). It forms the lining of the channel
  • The fourth transmembrane domain is the voltage sensor
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17
Q

Which voltage gated ion channel occurs first in evolution?

A

Potassium

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18
Q

What are the similarities between the Kv channel and the TPC, Cav and Nav channels?

A
  • TPC (two pore channels) family looks like two Kv subunits joined together – thought to have evolved by gene duplication – potassium channel like structures strung togethe
  • Cav and Nav look like four Kv subunits (four copies of original gene) joined together – thought to have evolved by gene duplication – potassium channel like structures strung together. The Cav and Nav have then mutated so not identical to Kv channels.
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19
Q

What is the structure of Cav and Nav?

A
  • The pore forming subunit of Cav and Nav is called the alpha subunit
  • Each of the segments that is not the alpha subunit is called a pseudo-subunit
  • Instead of having four separate subunits that come together the alpha subunit folds so that the four pseudo-subunits form the channel
  • Main difference between Cav and Nav is that instead of having four separate subunits they have four subunits joined together to make one long peptide
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20
Q

What are the Calcium channel subunits and what could the native channel possibly be?

A
  • A Cav 1.1-1.4
  • a Cav 2.1-2.3
  • a Cav 3.1-3.3
  • 4B 4a2(sigma) 8gamma subunits
  • Native channel possibly 1a: 1B: 1a2(sigma) - 3 subunits
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21
Q

What are the sodium channel subunits?

A
  • a Nav 1.1-1.9
  • 4B subunits
  • Native channel possibly 1a: 1B
22
Q

When are voltage-gated ion channels opened?

A

When the membrane depolarises

23
Q

What type of ion do voltage-gated ion channels select for?

A

Cations

24
Q

What is a hydration shell?

A

ring of water molecules that a positively or negatively charged ion attracts whilst in solution

25
Q

How do voltage-gated ion channels filter desired ions from undesired ones (e.g. Kv channel).

A
  • There are rings of charge around the mouth of voltage gated channels – help filter out desired ions from undesired. Ring of negative charge would attract cations and repel anions
  • Selectivity filter strips off the hydration shell from our ion
  • In the Kv channel the potassium ion interacts with the oxygen molecules in the channel – this means that the hydration shell is striped from the ion
  • If the ion is too small it won’t be able to interact with the oxygen and will keep it’s hydration shell
  • If the ion is too big it won’t be able to fit through the channel
26
Q

What is the knock on mechanism in a voltage-gated ion channel?

A

Our ion moves into the channel and knocks forward ions already in the channel

27
Q

How quickly do sodium channels open?

A

Open rapidly but inactivated after 1ms

28
Q

What states do sodium channels exist in?

A

 Resting state
 Open state
 Inactivated state

29
Q

What are transitions between states in sodium channels dependent on and when are they more probable?

A
  • Transitions between the states are dependent on voltage

- Changes between states are more probable as the membrane depolarises

30
Q

What happens with the opening and closing of the sodium channel?

A
  • Voltage sensor has charges in it – if you put a charged substance in an electrical field and then change the electrical field the charged particle will move – this happens with the voltage sensor – as we depolarise the membrane the voltage sensor moves and opens the gate of the channel
  • Sodium ions can now cross the membrane – as they cross it will increase the membrane potential even more – as it gets even more positive the inactivation gate will swing up and block the channel
31
Q

What is a ligand-gated ion channel?

A

Ion channel whose opening and closing is controlled by the binding of a ligand (neurotransmitter in the case of ligand-gated ion channels)

32
Q

What are the two main families of ligand-gated ion channels?

A 
- Cys-loop receptors:
 GABA^A
 Muscle nAChR
 Neuronal nAChR
 Glycine receptor 
 Nicotinic receptor
- Ionotropic (favour ions) glutamate receptors
33
Q

What is the structure of the muscle nicotinic receptor?

A
  • Transmembrane protein
  • 5 subunits which are all very similar
  • 2 alpha subunits
  • Beta subunit
  • Delta subunit
  • They are pentameric
  • In foetal tissues there is a gamma subunit/ adults – epsilon subunit
  • Two binding sites for acetylcholine located at the junction between the alpha subunits and their neighbouring gamma/epsilon or delta subunits
  • Cation channel – Na+, K+ and sort of Ca+ permeable
  • Each subunit has four TM domains and the second transmembrane domain from each subunit points inwards and forms the lining of the channel
  • Large extracellular end-terminal domains, contributes to the binding sites of acetylcholine
  • Have a big loop between the third and fourth TM domains which can be used to tether the protein to the cytoskeleton or regulate it’s activity
34
Q

How does fast, excitatory transmission happen in muscle nicotinic receptors?

A
  • Presynaptic nerve terminal releases acetylcholine from vesicles into synapse
  • Acetylcholine crosses the synapse and binds to nicotinic receptor on muscle membrane.
  • Opens built in sodium channel
  • Sodium enters the muscle cell through the nicotinic receptor
  • Causes depolarisation of membrane
  • This activates voltage-gated sodium channels in muscle membrane
  • Ends up with action potential being fired
  • Happens on a millisecond level and promotes action potential (hence fast and excitatory)
35
Q

Does fast excitatory transmission only happen in nerve to muscle communication?

A

No, it also happens in never to nerve communication

36
Q

What are the main method of fast excitatory transmission in the nervous system?

A

Ionotropic glutamate receptors

37
Q

Where does fast inhibitory transmission take place?

A

In nerve-to-nerve transmission

38
Q

What happens in fast inhibitory transmission?

A
  • GABBA receptors activated on post-synaptic membrane
  • GABBA is a chloride channel
  • Cl- enters post-synaptic neurone membrane
  • Membrane becomes hyperpolarised making excitation more difficult
39
Q

How does BABAa help as a drug target?

A

useful with anxiety, epilepsy (can dampen the excitatory effects), main targets of general anaesthetics

40
Q

How does Muscle nAChR (nicotinic receptor) act as a drug target?

A

muscle relaxation in surgery

41
Q

How does neuronal nAChR (nicotinic receptor) act as a drug target?

A

nicotine addicton – how nicotine patches work, (potential for treatment with psychiatric, neurodegenerative disorders)

42
Q

What may a glycine receptor be a good target for

A

analgesic drugs

43
Q

What drugs is the 5HT3 receptor a good target for?

A

anti-emetic drugs (treats nausea) (often used in chemotherapy)

44
Q

Why aren’t voltage gated channels properly classified as receptors?

A

because they don’t need an agonist to bind to open them

45
Q

What are the three ways drugs can effect ion channel function?

A
  1. Binding to the channel-protein itself, either to the ligand-binding site of ligand-gated channels or to other allosteric site, the drug molecule plugs the molecule physically, blocking ion permeation
  2. By an indirect interaction, involving an activated G protein subunit or other intermediary
  3. By altering the level of expression of ion channels on the cell surface. For example, gabapentin reduced the insertion of neuronal calcium channels into the plasma membrane
46
Q

How do drugs target enzymes?

A

by acting as a competitive inhibitor of that enzyme or in other cases the binding is irreversible and non-competitive

47
Q

What do kinase-linked and related receptors mainly respond to?

A

to protein mediators

48
Q

What is the structure of kinase-linked and related receptors?

A

They are made up of an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix. In many cases the intracellular domain is enzymic in nature

49
Q

In nicotinic receptors what must both binding sites do in order for the receptor to be activated?

A

Bind acetylcholine molecules

50
Q

What changes the channel from being cation permeable (excitatory) to anion permeable (inhibitory) in a nicotinic receptor?

A

a mutation of a critical residue in one of the transmembrane helixes (2)

51
Q

What is prenylation?

A

The reaction in which the gamma subunit in a g protein is anchored to the membrane through a fatty acid chain, coupled to the G protein

52
Q

What are the main targets for G proteins?

A
  • Adenylyl cyclase
  • Phospholipase C
  • Ion channels
  • Rho A/ Rho kinase
  • Mitogen-activated protein kinase

Drugs: from molecules to man (22 decks)

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