Phil Flashcards
VGICs structure, GPCRs, M-current, H-current, diseases, drug targets
Function of the m-current
controls firing pattern of APs (spike frequency adaptation)
Function of the h-current
Cardiac pace-making in sino atrial node
Oscillatory regulation in thalamus (controls the transition from awake to sleeping, which is why dysfunction is associated with seizures while falling asleep)
Responsible for rebound firing post inhibition
What are theraputic modulations of the m-current?
Enhancing m-current (with retigabine) is a theraputic for epilepsy (retigabine enhances KCNQ2&3 by binding pore region and stabilizing open conformation, similar to PIP2) (IVA73 restores coupling of voltage sensor to channel, specific to KCNQ2)
Enhancing m-current with GABApentin is theraputic for developmental epileptic encephalopathy (acts on KCNQ3&5, similar to retigabine)
Disinhibiting m-current (with DHEAS) is theraputic for inflammatory pain (opposes mAChR inhibition of m-currents, can compensate for PIP2 loss by stabilizing open current)
What are therapeutic modulations of h-current?
Blocking Ih (with ZD7288) decreases neuropathic pain, since there is increased h-current in chronic pain. This is thought to be mediated by HCN2 since HCN2 KO is also analgesic
Blocking Ih: Anasethetics act through Ih (HCN1 sensitive to ketamine, propofol, and Isoflurane block), by shifting activation -ve
HCN blockers can be used to reduce heart rate (Ivabradine blocks HCN4)
How do GPCRs modulate the m-current and h-current?
mAChRs: modulate m-current by cleaving PIP2 (if M1/M2) or through IP3/DAG (if B2 receptors activated) (PIP2 increases current, Ca2+ closes them)
B-adrenergic receptor: modulate h-current by Gs-> adenylyl cyclase-> cAMP via the CNBD (cAMP increases current)
What diseases arise from m-current dysfunction?
- Peripheral nerve excitability
- Benign neonatal familial seizures
- early onset-encephalopathy
What diseases arise from h-current dysfunction?
- Familial sinus bradycardia
- Sinus node disease
- Idiopathic Generalized Epilepsy
What drugs target the m-current and how?
- Oxo-M (mAChR agonist and inhibits the m-current)
- iRap (hydrolyses PIP2 thus inhibitng m-current)
- retigabine (binds pore forming regions and stabilises state to inc open probability, shifts activation to more hyperpolarising levels, restores coupling of voltage sensor to opening of gate- potentiates m-current)
- ICA73 (interacts with voltage sensor on KCNQ2 specifically, lowers threshold for activation, potentiates m-current)
- Gabapentin (treats KCNQ2 developmental epileptic encephalopathy, similar binding site to retigabine, enhance current flow in mutated subunit, potentiates m-current
- DHEAS (reduces ability of mAChR to inhibit channels, compensates for PIP2 loss by stablising open channels, attenuates pain- potentiates m-current)
What drugs target the h-current and how?
- 5-HT, NA (enhance Ih by causing increased cAMP)
- cAMP (enhances Ih, binds iCTD thus disinhibits HCN)
- ZD-7288 (inhibitor, neuropathic analgesic, reduces increased HCN2-mediated Ih current in B fibres)
- extracellular Cs+ (inhibitor)
- Ivabradine (use dependent inhibitor, treats cardiac dysrhythmia, treat LoF HNC4 mutation)
- Ketamine (supress current flow thru HCN1& HCN1/2 due to shifting activation curve left so need more hyperpolarisation to activate channels, inc temporal summation from inc resistance, increases unconsiousness)
- Propofol (supress Ih through HCN1, similar to ket)
- Isoflurane (supress Ih through HCN1, inc temporal summation of EPSPs in pyramidal dendrites)
iCTD= intracellular carboxy terminal domain
Use dependent bc as you depolarise the K+ efflux drives ivabradine closer to its binding site- as you hyperpolarize the cell the current is mainly driven by Na+ so pushes Iva out, iva binds tightly to pore but part of the block is also electrostatic
HCN1 confers ketamine sensitivity
What relationship does the Ih (h-current) have with noradrenaline?
- NA increases Ih current (resulting in depolarisation) through beta receptors
- Doesn’t increase amount of channels at the membrane, just seems to shift activation curve to more depolarised
How does PIP2 gate KCNQ channels?
It binds the S2/3 linker region when channel is closed, and when channel is open (voltage sensor moved) it binds the S4/5 region and holds the channel open
Explain the WDW experiments?
Water-Dox-Water: doxycycline binds promotor and inhibits expression of mutant protein that supresses m-current; if you supress expression into adulthood and then remove doxycycline you can observe the affect of the mutation on the m-current in a non-impaired hippocampus
What does the status epilepticus model show?
Induced by kainic acid onto entorhinal cortex neurons; shows how excitability itself can lead to changes in channel function (resting potential was more hyperpolarised, greater dendritic excitability for same stimulus) See decreased H-current channels, thus resistance is increased
