BB Lecture 17: Voltage-Dependent Channels

Question 1

What are inward rectifiers?

Answer 1

K+ selective channels
selection via selectivity filter (p-loop with signature sequence) that is only narrow enough for a single, dehydrated K+ ion to pass through (but too wide for a Na+ ion to be stabilized by the carbonyl groups)

Question 2

How is the K+ ion dehydrated to be able to pass through an inward rectifier?

Answer 2

carbonyl groups in the selectivity filter (found in the P-loop) are positioned to interact with a dehydrated K+ ion to compensate for the “cost” of the dehydration

Question 3

How are inward rectifiers voltage dependent?

Answer 3

the acidic residues on the inside of the pore are accessible from the intracellular side so various species of cations can interact and block the pore (because they cannot get through the selectivity filter)
these can become unblocked when the membrane becomes hyperpolarized and K+ ions are driven to go into the cell and unblock the channel

Question 4

What are voltage-gated channels?

Answer 4

ion selective: normally either for K+, Na+, and Ca2+

most all open upon membrane depolarization

Question 5

How do the voltage sensors regulate K+ voltage-gated channels?

Answer 5

when Vm is well polarized (negative) S4 helices are positioned near the intracellular side of the membrane (attracted to the uncompensated negative charges in the cytoplasm) pinching the S6 helices together near the intracellular entrance to the pore to prevent ion flow
upon membrane depolarization the negative charges near the inner face of the membrane are fewer so S4 is less attracted and moves to the outer leaflet
if all four of the S4 helices do this, the activation gate is pulled open and K+ ions flow

Question 6

What is the activation gate?

Answer 6

the point where all four S4 helices are near the intracellular side of the membrane and the S4 helices are pinched together
must be open for the channel to pass a current

Question 7

How are voltage-gated K+ channels “turned off”?

Answer 7

1. some stay open for as long as the membrane remains depolarized and returns to closed formation when membrane potential returns to resting value (deactivation)
2. others stop conducting soon after activation (even if the membrane is still depolarized because of inactivation)

Question 8

Describe inactivation of a K+ voltage-gated K+ channel.

Answer 8

similar to inward rectification
basic amino acids at the N-terminus of each subunits (“ball-and-chain”) are exposed when the activation gate is opened
the balls are positively charged and are able to lodge themselves in the pore so that (even upon membrane repolarization and return of the S4 voltage sensors to the inner leaflet) activation gate does not close until the ball-and-chain vacate (normally must be attracted by a relatively negative interior of the membrane)

Question 9

What is de-inactivation?

Answer 9

the process of removing an inactivating particle from a channel following the inactivation of the channel
not instantaneous
even after membrane repolarizes, there will be a delay before the channel can activate again (range of milliseconds)

Question 10

How do Na+ and Ca2+ voltage-gated channels differ from K+?

Answer 10

• formed by a single polypeptide with four domains (six helices each) rather than the four subunits of the K+
• have selectivity filters on their P-loops but details are less understood
• lack ball-and-chain motif (but do use positive charges on teh long intracellular linkers to block pore)