Ion channels

Question 1

What stimuli control ion channels’ gating?

Answer 1

• some channels respond to multiple stimuli
• temperature
• mechanical deformation
• membrane potential
• extracellular chemicals (taste, olfaction, neurotransmitters)
• intracellular second messangers (ATP, cAMP, Ca2+)

Question 2

Voltage gated channels of the Kv, Nav, and Cav families have _____ membrane spanning domains, each with ______ alpha helices.

Answer 2

four membrane spanning domains; six alpha helices (S1 - S6)

Question 3

What structures do the Nav and Cav channels contain?

Answer 3

• the four domains are linked into a single polypeptide
• S4 helices have positively charged residues (lys or arg) at every third position (sense voltage)
• S5 and S6 helices and the “P loop” (connects them) form the ion conducting pathway

Question 4

What are ionotropic receptors?

Answer 4

neurotransmitter receptors are directly coupled to ion channels

Question 5

What are pentameric ligand gated channels?

Answer 5

• ionotropic receptor
• lys-loop family of neurotransmitter receptor channels (GABAaRs, GlyRs, etc)
• heteropentamers
• each subunit has four transmembrane alpha helices (M1 and M4)
• M2 assembles around the central, ion-conducting pathway
• channels are selective for permeation of chloride, or allow both sodium and potassium

Question 6

CLC chloride channels

Answer 6

• has an ion permeation pathway
• each permeation pathway can gate open and closed independently of one another
• some in this family are H+/Cl- exchangers
• important for stabilizing the resting membrane potential

Question 7

Aquaporin water channels

Answer 7

• tetramers where each subunit contains a permeation pathway for water molecules
• anti-ion channels since they exclude all ions including protons
• e.g. in kidney

Question 8

Which channels are selective? (Kv, Cav, Nav)

Answer 8

Kv and Cav are selective. Nav is moderately selective

Question 9

How is charge important for what passes through a channel?

Answer 9

• channels are cation or anion selective

- ionic valence is also important

Question 10

How are ions dehydrated in order to pass through a channel pore?

Answer 10

• ion is stabilized within the pore by energetic interactions with the amino acids forming the pore (but not completely or they would get stuck)

Question 11

What is one factor that can increase channel pore selectivity?

Answer 11

if an ion interacts with multiple sites while traversing the channel pore

Question 12

Describe the gating for Kv.

Answer 12

• the activation gate (intracellular side) can rotate around a center pivot point
• rotation is controlled by a “voltage-sensing” charge
• closed when cell has negative potential (deactivation)
• open when the inside is made positive causing K+ ions to flow out of the cell (called activation)

Question 13

Describe Nav’s activation gate.

Answer 13

• on intracellular side
• closed at negative potentials
• open when the cell becomes positive and Na+ flows in

Question 14

Describe Nav’s deactivation gate.

Answer 14

• on intracellular side
• open at resting potential (activation gate occludes access to a site within the inner end of the pore at which the inactivation gate can bind)
• after the activation gate opens, the inactivation gate closes (called inactivation)

Question 15

Describe the selectivity filter for Kv and Nav.

Answer 15

occurs within a central, ion conducting pathway formed by the four Kv subunits or four repeats of Nav (central pathway surrounded by S5 and S6 helices and connecting P loop)

Question 16

What performs the voltage sensing for Kv?

Answer 16

the S4 helices

Question 17

What forms the inactivation gate of Nav channels?

Answer 17

cytoplasmic loop connecting repeats III and IV

Question 18

Why do many channel modifying reagents have access to their sites of action only from one site of the membrane?

Answer 18

• the location of the selectivity filter near the extracellular side
• the vestibule nearer the intracellular side of the Kv/Nav channels
• the location of the activation/inactivation gates near the intracellular side

Question 19

Where does tetrodoxin (TTX) bind to Nav?

Answer 19

The entrance of the pore above the Nav selectivity filter

Question 20

Where does lidocaine bind to Nav?

Answer 20

• must block the channel fro the intracellular side but protonated form cannot cross the membrane
• requires the activation gate to open and the inactivation gate not to be closed to enter
• thus the nerves with more activity are blocked first/preferentially