Drug Targets 2

Question 1

What percentage of drugs target ion channels?

Answer 1

About 11%

Question 2

What are drugs targeting ion channels important in treating?

Answer 2

Cardiovascular disorders

Question 3

Why can’t ions penetrate lipid bilayers?

Answer 3

They are charged

Question 4

How does an ion channel help ions move through?

Answer 4

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

Question 5

What mechanism do ion channels work through?

Answer 5

Diffusion

Question 6

What are the basic properties of all ion channels?

Answer 6

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

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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

Question 11

What are the different types of gating?

Answer 11

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

Question 12

What are ion channels classified by?

Answer 12

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

Question 13

How are ligand-gated channels named?

Answer 13

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

Question 14

What is the basic working of voltage gated ion channels?

Answer 14

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

Question 15

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

Answer 15

• Calcium channels (Cav)
• Sodium channels (Nav)
• Potassium channels (Kv)

Question 16

What is the structure of the potassium channel?

Answer 16

• 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

Question 17

Which voltage gated ion channel occurs first in evolution?

Answer 17

Potassium

Question 18

What is the selectivity filter?

Answer 18

The part of the ion channel that selects between various ions on the basis of charge and size.

Question 19

Why don’t all small ions also fit through the ion channel?

Answer 19

• Around the mouths of some ion channels is found a ring of charged amino acids
  ○ have the opposite charge to the type of ion the channel is selective for
  e.g. a cation channel will have a ring of negative charges.
• This ring of charge serves to repel ions of the opposite charge type.

Question 20

What is a transmembrane protein?

Answer 20

it crosses the membrane six times fully, so six transmembrane domains and it between the 5th and 6th transmembrane domain there’s a bit that dips into the membrane but doesn’t go all the way through and this membrane dipping domain is what forms the lining of the channel

Question 21

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

Answer 21

• 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.

Question 22

What is the structure of Cav and Nav?

Answer 22

• 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

Question 23

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

Answer 23

• 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