PHYSL 371 Neuronal Ca2+ Channels

why is calcium so important

it is essential for cellular signalling

what does Ca2+ activate

enzymes (such as protein kinases and proteases) and NT release through binding on synaptic vesicles

is there more Ca2+ inside the cell or outside

there is a much larger concentration outside the cell (barely any inside)

why is the large concentration gradient of Ca2+ between the ICS and ECS important

it allows the inside of the cell to detect even small changes in Ca2+ level making it more sensitive and able to respond more quickly/efficiently

what direction will Ca2+ move when a channel opens

always into the cell

what are 4 reasons for why low Ca2+ concentration on the ICS being important

1. sensitivity (cell detects any changes)

2. speed (fast response because gradient is so large)

3. selectivity (activates only local responses where the Ca2+ entered)

4. safety (prevents spurious activation because they are only affected within a certain domain)

during an AP, what ions enter the cell bodies

Ca2+ enters through Ca2+ channels and Na+ enters through Na+ channels

what does elevated Ca2+ levels activate during an AP

Ca2+ activated K+ channels such as BK and SK channels

why is activation of Gk,Ca's (Ca2+ activated K+ channels) important

BK channels help to depolarize the neuron while SK channels help to limit receptive firing

what are the 2 main functions of Ca2+

1. drive excitation by changing membrane potential

2. come in at nerve terminals and drive fusion of synaptic vesicles to release NTs

what are the 2 categories of voltage gated Ca2+ channels

1. high voltage activated (HVA) channels

2. low voltage activated (LVA) channels

what are the kinds of voltage gated Ca2+ channels classified by

electrical behaviour and pharmocology

high voltage activated (HVA) channels

channels start to activate near AP threshold (about -40 mV)

what are the types of high voltage activated (HVA) channels

L-, N-, P-, Q-, R- channels

low voltage activated (LVA) channels

start to activate near RMP (about -70mV)

what is a type of low voltage activated (LVA) channels

T channels

what is the structure of Ca2+ channels

made up of 6 alpha-helical TM segments, tetrameric (4 copies of channel forming domains linked by the same gene)

what channel is similar to the structure of Na2+ channels

Na+ channels

what transmembrane subunits make up the voltage sensor of the channel

S1-S4

what transmembrane subunits make up the selectivity filter of the channel

S5-S6

what is the identity of a Ca2+ channel determined by

the core pore forming alpha subunit

what subunits do L,N,P,Q, and R alpha subunits associate with

a beta and an alpha 2 delta

what subunits do T alpha subunits associate with

they do not assemble with significant numbers of subunits and instead assemble on their own

what do some L-type channels associate with

a gamma subunit

how many genes code for Ca+ channel types

3 sets of genes that in total code for 10 proteins where majority code for HVA channels and come coding for LVA

what are T channels conductances relative to other types of channels

low conductance and prominent inactivation

what are N channels conductances relative to other types of channels

large conductance with intermediate inactivation

what are L channels conductances relative to other types of channels

large conductance with little to no inactivation

where are L type channels found

skeletal, cardiac muscle, and to some extent in nerve

what are L type channels useful for

biochemical studies in muscle and allowing for a long cardiac AP

where does the L type channel nomenclature come from

because they have Large conductance and are Long lasting (due to slow inactivation)

what voltage activates L type channels

high voltage therefore around -40mV (need for a strong depolarizing stimulus)

where are N type channels found

in the nervous system along with P and Q channels

what are N type channels useful for

allow for Ca2+ to enter synaptic terminals and trigger NT release

where does the nomenclature for N type channels come from

Neuronal, Neither L or T, iNtermediate

what is the activation voltage for N type channels

in between L and T (but still HVA)

what are some examples of G-protein coupled agonists

opioids, alpha 2 adrenergic, GABAb agonists

what happens when these G-protein agonists bind to their receptor

they imitate a G-protein signalling cascade which decreases the probability of N-type channels opening

what are the 2 mechanisms which G-protein coupled agonists can decrease N-type channel opening probability

1. direct: G-protein beta-gamma subunit interaction with N-type channels due to voltage activation

2. indirect: voltage-insensitive modulation of the channel via second messengers

how do G-protein coupled agonists can decrease activity

G beta gamma i subunit gets released off the G-protein and binds directly to the voltage gated N-type channels which suppresses them from opening and allowing Ca2+ to enter therefore leading to decreased NT release

what does the G alpha subunit do

effects cAMP signalling downstream

where does the G beta gamma I subunit associate

directly in between the 3rd and 4th repeat/domain

what does the T type channel nomenclature come from

Tiny unitary conductance and Transient activation (rapid inactivation)

what voltage activates T channels

negative voltage activation (LVA)

what is required to remove inactivation of T type channels

strong hyperpolarization because they activate at negative voltages to begin with

what is window current

the currents in a range where inactivation is incomplete and not all channels are in the inactivated state therefore can still deactivate instead

window current for T type channel inactivation

T type channels can generate depolarizing current when cells are in the window current voltage range and drive excitation

how do T channels contribute to bursting

they contribute to the depolarization that occurs between bursts because the voltage drops into the window current voltage range

why does window current happen

Ca+ activated K+ channels will begin to begin to depolarize the cell preventing all the T channels from becoming inactivated at positive currents therefore allowing them to become activated again around RMP

what do T type channel blockers do

suppress excitation and can be used to therapeutically treat specific types of seizures

enthosuximide

used to treat absence seizures