Lecture 16: Ion Channel Physiology and Pharmacology

What channels do neurotoxins and anesthetics block?

block Na+ channels

List the neurotoxins.

• tetrodotoxin (TTX)
  saxitoxin (STX), shellfish poisoning

• mu-conotoxins, venomous marine snails

What are some examples of local anesthetics?

• procaine

• lidocaine

• tetracaine

What is local anesthesia?

injected or infused right at the site where anesthesia is needed

True or False: Local anesthetic action is use-dependent.

true

What is meant by local anesthetic action being use-dependent?

inhibition of Na+ current increases with repetitive stimulation/firing

True or False: Inhibition increases with increasing frequency of stimulation. Inhibition develops in a time-dependent fashion with repetitive stimulation.

true

Ca2+ channels contribute to action potentials in some cells. What are these cells?

• cardiac cells

• smooth muscle cells

• secretory cells

• some neurons

Review the following process:

1. gating of Ca_v channels is slower than that of Na_v channels

2. more sustained depolarizing current

3. longer-lived AP

What are Ca2+ channels classified based on?

kinetics

What are the two types of Ca2+ channels?

• L-type

• T-type

What do L-type channels underlie?

underlie long-lived plateau AP phase

What do L-type channels do?

increase Ca2+ influx for contractile and secretory responses like neurotransmitter release

What are T-type channels activated at?

activated at more negative voltages than L-type

What do T-type channels have roles in?

repetitive firing in cardiac cells and neurons

When do delayed outward rectifier currents (I_K) activate with?

activate with lag phase (Hodgkin-Huxley model)

Briefly describe the delayed outward rectifier current.

outward current rises steeply at positive voltages

True or False: Transient A-type K+ current (I_A) is activated and inactivated over a rapid time scale.

true

When is transient A-type K+ current (I_A) activated?

activated in negative V_m range (during afterhyperpolarization)

What is transient A-type K+ current important in?

important in determining interspike interval between repetitive APs

What are the two types of “ball-and-chain mechanisms” of inactivation for K_v channels?

• the N-terminal domain ball moves in and blocks the channel

• the B subunit moves in and blocks the channel

What does the P_o of large-conductance Ca2+-activated K+ channels (BK_Ca) increase with?

• intracellular calcium concentration

• positive voltage

What does BK_Ca do?

• help counteract repetitive excitation and Ca2+ loading

• return V_m back towards V_m

• drive termination of bursts of repetitive APs

What are small-conductance Ca2+-activated K+ channels (SK_Ca) activated by?

activated by Ca2+-binding protein calmodulin

True or False: SK_Ca are voltage-insensitive.

true

What do inward-rectifier potassium channels (K_ir) do?

keep V_rest close to E_k

There is an intracellular block of K_ir channels by Mg2+ at positive V_m values. What is the downward pathway?

1. internal side becomes more positive

2. relatively more negative charge on external side

3. Mg2+ drawn close to negative charge and plugs up the channel

True or False: K_ir channels only pass current at negative V_m values due to the intracellular block by Mg2+ when V_m > 0 mV.

true

True or False: K_ir channels are not directly voltage-gated, even though the V_m value plays a critical role in whether K+ flux occurs.

true

What do GIRKs stand for?

G protein-activated inwardly rectifying K+ channels

What are GIRKs opened by?

by binding of beta-gamma subunits of G-proteins

True or False: The values at which V_m would need to be at in order for there to be inward current very rarely occur physiologically.

true

In a typical V_m range near V_rest, what does an increase in outward K+ current lead to?

hyperpolarization

What are K_ATP channels activated and inhibited by?

• inhibited by ATP

• activated by ADP

At rest, are K_ATP channels open or closed?

open

What is the process in B cells with glucose uptake and K_ATP channels?

1. increased ATP:ADP ratio

2. K_ATP channels inhibited

3. V_m depolarizes

4. voltage-gated Ca2+ channels activated

5. Ca2+-dependent insulin secretion

What is an accessory subunit to K_ATP channels?

sulfonylurea receptor

What does sulfonylurea binding to K_ATP channels do?

closes K_ATP channels

What is sulfonylurea used to treat?

used in treatment of type-2 diabetes

How do sulfonylureas function?

stimulate insulin release via K_ATP channel closure