ion channel diversity I

channels found in dendritic shafts

• voltage gated sodium

• N/P/T type voltage gated calcium channels

• select potassium channels eg Kv4.2

why are N type calcium channels found in the dendritic spines

• need calcium influx for neurotransmitter release

how are ion channels regulators of excitability

• affect size, shape, frequency and pattern of AP

which calcium channels are L type

• 1.1→ 1.4

which calcium channels are N and P type

2.1→2.3

which calcium channels are T type

• low voltage activation

• 3.1→3.3

what is the minimal requirement for forming an ion channel

S5-P-S6 motif

beta subunits of Kv channel

• 4

• increase trafficking and surface expression

• modulate channel gating

selectivity filter

• p loops form external mouth and lining of the channel pore

• glutamate residues indicative of calcium channels

what acts as the voltage sensor

• pos charged arginine or lysine of S4

• when S4 moves up it couples to mechanism of channel opening

channel opening activation

• movement of S4 with negatice charges of S1,2,3

• displaces S4-S5

• causes channel opening 

inactivation of channel

• n type - slow, ball and chain 

• c type - fast

S6 subunit function

• channel inactivation

• slow constriction of channel pore

electrochemical coupling

• charged amino acids move through membrane electrical field

• couples electrical work to process of channel opening

state dependent blockers

• local anesthetics, L type CaV antagonists

• bind to channels either resting or open

agents that modulate ion channels and how

• metal ions, organic molecules, venom derived peptides

• block channel pore, modify gating, state dependent drug action

which channels are targeted for chronic pain

• sodium channels

what drugs use na channels as targets

• anaesthetics

• anticonvulsants

• antiarrhythmic agents

TTX-s channels

• eg Nav1.7

• blocked by low concentrations of TTX

• rapid inactivation, found in DRG and involved in chronic pain

TTX-r channels

• eg Nav1.8

• require higher conc of TTX to inactivate

• smaller amplitude, rate of inactivation, larger stimulus required

what does TTx bind to 

• EC region of IS5-S6 loop 

amino acid difference between IS5-6 loop for TTX channels

• in TTX-s - aromatic eg tyrosine and phenylalanine

• in TTx-r polar eg cysteine or serine

role of transmembrane beta subunits

• modulate channel gating

• regulate cell surface expression

• function as cell adhesion molecules CAMs with Ig domain