Ion Channels Flashcards
Ion channel definition
Mem proteins that open/close (gate)
When open, selective
In PM and organelles
Gating controlled by many stimuli (temperature, mechanical deformation, membrane potential, extracellular chemicals, intracellular second messengers). Some respond to multiple stimuli.
Kv, Nav, Cav families
Have 4 membrane spanning domains, each of which contain six alpha helices (S1-S6).
S4 have pos charged residues (lys or arg) at every 3rd position, they “sense” voltage
S5 and S6 and connecting P loop assemble to form the ion conducting pathway & selectivity filter.
Nav and Cav families
4 domains are linked into a single polypeptide
Kv family
Each domain is a separate polypeptide, 4 of these assemble to form the channel.
NT receptor
Ionotropic
Can be directly coupled to the ion channels (receptor and channel part of same protein).
NT receptor
Metabotropic
Activate second messenger pathways.
Pentameric ligand gated channels
Ionotropic NT receptors.
Cys-loop family of NT receptor channels. Including GbA nACh.
They are heteropentamers.
Heteropentamers
Contain 4 TM alpha helices (M1-M4) per subunit. M2 helices around a central, ion-conducting pathway.
Selective for either Cl- or Na and K (slight preference of Na>k)
Tetrameric ligand gated channels
Ionotropic glutamate receptors.
NMDA receptors: 2 subunits bind glutamate. 2 bind glycine.
Chloride channels
Of the CLC family are dimers (each subunit has ion permeation pathway). Each pathway can open/close independently.
There is also another gate that controls both paths simultaneously.
A member of the fam is: H+/Cl- exchangers (imp for stabilizing resting mem. potential).
Aquaporins
Water channels.
Tetramers, each subunit has a permeation pathway (kidney or where rapid h20 exchange necessary).
Assembly of 4 subunits produces a central pore that allows ion permeation and can be gated between open/closed.
What determines channel selectivity?
- ) Charge (+ or -, valence)
- ) Size
- ) Dehydration (ion will get dehydrated before entering and this is energetically unfavorable, stabilized in pore by interactions with AA forming the pore)
- ) Multiple binding sites (increases selectivity) (ion interacts with multiple sites)
Repolarization
more negative.
Activation gate
rotates around center pivot point, controlled by voltage-sensing charge (if cell is neg inside the gate is held closed and current is zero. inside becomes pos, gate swings open)… activation
Deactivation
inside of cell has gone back to neg, so gate closes, current decays.
Reverse of activation.
Kv Nav channels
Activation gate, activation, deactivation
Nav channels
Have inactivation and activation gate.
Inactivation gate is open at resting potential because activation gate occludes access to site where it would bind… after activation gate closes inactivation gate opens Get inactivation and decay of current during maintained depolarization.
Inactivation is slow.
Kv and Nav selectivity
in central ion conducting pathway formed by 4 K subunits or 4 repeats of Na.
S6
S6 does hinge motion around a conserved glycine (activation gate opening is likely inner ends of S6 doing this hinge motion)
Closed activation gates occlude access to vestibule where ions pass before going through selectivity filter nearer extracellular side.
S4
Pos charged S4 translocate in response to voltage charges across the membrane (Activation).
Inactivation gate
of Nav formed by cytoplasmic loop which connects repeats III and IV (folds over inner end, intracell side).
Sidedness of agents
Because of selectivity filter near extracell. side and vestibule near intracell. side. and activation/inactivation near intracell.
So many channel modifying reagents only have access to their sites on one side (might require channel to be open).
Tetrodotoxin
Binding is independent of position of activation/inactivation gates. No effect when added intracellularly.
Binds on extracell side just inside selectivity filter.
Lidocaine
Goes between protonated (dominant at physiological pH) and deprotonated (CAN cross).
No effect from ECF, can block channel from ICF side.
Only occurs if protonated lidocaine can access the vestibule (activation gate must be open), inactivation gate can’t be closed.
STATE DEPENDENT drug.
