Voltage gated Calcium channels

Calcium entry triggers

• NT release at synapse

• muscle contraction

• gene transcription

• modulation of excitability

Depolarization of calcium allows

Ca+ to flow in

Calcium channels are activated by

depolarization

Fatt and Katz experiment 

they replaced Na+ with choline outside the crustacean motor neurons and the action potentials persisted because these muscles use Ca+ to generate an action potential

Addition of TEA in the Fatt and Katz experiment:

TEA blocks K+ channels reducing hyper polarization (less k+ coming in), causing the ca2+ current to spike

can Ba2+ pass through the Ca2+ channels?

yes, increasing Ba2+ increased action potential. (so can Sr2+)

Mn2+ is used to

block ca2+ channels, blocking excitability 

EXCESSIVE Ca2+ causes channel

inactivation

INCREASED Ca2+ channels causes activation of Ca2+ dependent K+ channels causing

repolarization or hyperpolarization

Sites of regulation of Calcium channels, consists of

4 repeating domains 1-4 with 6 transmemb segments s1-s6

S4 segement acts as a

voltage sensor (has pos charged amino acids

Loop between S5 and S6 lines the i

on pore conducting

Sites of regulation:

GBy (G protein By subunits)

G-protein coupled receptors are activated, GBy can bind to the channel and inhibit Ca2+ current

less NT release 

Sites of regulation:

PKC (protein kinase C)

phosphorylates the channels increasing activity 

Sites of regulation:

SNARE proteins 

part of vesicle fusion machinery, interact with Ca2+ channels to couple depolarization with NT release (vesicles fuse when ca2+ enters)

Sites of regulation:

Ca2+/CaM (calmodulin)

binds to intracellular tail when Ca2+ enters and mediates Ca2+ dependent inactivation or facilitation 

CBD Calcium binding domain

site where Ca2+ or CaM attaches to regulate channel behavior

Properties of Voltage Gated Calcium Channels

1

voltage gated (open when memb depolarizes)

Properties of Voltage Gated Calcium Channels

2

found in every excitable cell (neurons, muscles, anywhere action potentials occur)

Properties of Voltage Gated Calcium Channels

3

Voltage dependent gates

Properties of Voltage Gated Calcium Channels

4

delayed opening with depolarization (open more slowly than Na+ channels)

Properties of Voltage Gated Calcium Channels

5

rapid close after depolarization (inactivate quickly once memb potential restored

Properties of Voltage Gated Calcium Channels

6

slow inactivation during maintained depolarization 

Properties of Voltage Gated Calcium Channels

7

moderate ion selectivity

Properties of Voltage Gated Calcium Channels

8

can be blocked by agents in and out of cell

Properties of Voltage Gated Calcium Channels

9

translate electrical signals into chemical signals (like gene expression)

Subunit functions:

a1 subunit

ion conducting pore 

contains voltage sensor (S4) and selectivity filter 

Subunit functions:

a2theta

accesory subunits, how quickly channels activates or inactivates 

target for gabapentin bind tp this channel 

Subunit functions:

Beta subunits

found on intracellular side 

regulates voltage dependance and kinetics 

Subunit functions:

y subunits

modulate gating and anchor complex

a2beta-1 subunit play role in 

channel function and synapse formation (synaptogenesis)

Ca2+ channels typically open at more _____ potentials compared to Na+

depolarized, open after Na+ channels

Ca2+ current is (faster/slower) and (long-lasting/short)

slower and long lasting

Na+ current is (faster/slower) and (long-lasting/short)

faster activation and inactivation (spikes)

Ca2+ current amplitute is smaller than Na+ because extracellular is

low so the driving force is smaller

Graph C (chromaffin)

cell depolarizes, current increases (channels open), then decreases because driving force of drops (bc the memb potential is reaching equalibrium potential) causing channels to close

Slide 10

Graph A: cardiac pacemaker (no Na+ channels here)

only voltage gated Ca2+ channels generate rising phase of pacemaker potential