Lecture 16: Ion Channel Physiology and Pharmacology

What are toxins that block Na⁺ channels?

• TTX

• STX

• mu-conotoxins

What are local anesthetics that block Na⁺ channels?

• procaine, lidocaine, tetracaine

  • injected or infused right at site where anesthesia is needed

• action is use-dependent

  • inhibition of Na⁺ current increases with repetitive stimulation/firing

Describe the pathway that Ca²⁺ channels use to contribute to APs?

gating of Ca_v channels is slower than that of Na_v channels → more sustained depolarizing current → longer-lived AP

How are Ca²⁺ channels classified?

based on kinetics

Describe the difference between L-type and T-type Ca²⁺ channels?

L-type

• underlie long-lived plateau AP phase

• Ca²⁺ influx for contractile and secretory responses

T-type (transient)

• activated at more negative voltages than L-type

• roles in repetitive firing

How does delayed rectification look in K_V channels?

Delayed outward rectifer

• activates with lag-phase

• outward current rises steeply at positive voltages

Describe transient A-type K⁺ current (I_A)?

• activated and inactivated over rapid time scale

• activated in negative V_m range (during hyperpolarization)

• important in determining interspike interval between repetitive APs

Describe the findings in the large conductance Ca²⁺-activated K⁺ channels.

• P_o increases with increasing intracellular Ca²⁺

• P_o increase with positive voltage

• Help counteract repetitive excitation and Ca²⁺ loading

  • return V_m back towards V_rest

• drive termination of bursts and repetitive APs

Describe the findings in the small conductance Ca²⁺ -activated K⁺ channels.

• activated by Ca²⁺ -binding protein calmodulin

• voltage-insensitive

What is true of inward-rectifying K⁺ channels?

• keep V_rest close to E_K

• only pass current at negative V_m values due to the intracellular block by Mg²⁺ when V_m > 0 MV (when E_K = 0 mV)

• they are not directly voltage-gated, even though V_m value plays a critical role in whether K⁺ flux occurs

What does an intracellular block of channel by Mg²⁺ at positive V_m values show?

internal side becomes more positive → relatively more negative charge on external side → Mg²⁺ drawn close to negative charge, plugs up channel

What is true of GIRKs?

• opened by binding of By subunits of G-proteins

• values are which V_m would need to be at in order for there to be inward current very rarely occur physiologically

• in typical V_m range near V_rest = increase in outward K⁺ current → hyperpolarization

What is true of K_ATP channels?

• inhibited by ATP and activated by ADP

• K_ATP channels are open at rest

How do K_ATP channels in pancreatic B-cells, with glucose uptake, function?

increased ATP:ADP ratio → K_ATP channels inhibited → V_m depolarizes → Voltage-gated Ca²⁺ channels activated → Ca²⁺ dependent insulin secretion

What is the sulfonylurea receptor?

accessory subunit to K_ATP channels

What closes K_ATP channels?

sulfonylurea binding

What is sulfonylurea used in?

treatment of type-2 diabetes to stimulate insulin release via K_ATP channel closure