Voltage-Gated Sodium Channels Flashcards
(13 cards)
Diversity of Nav channels
- 9 isoforms of alpha
- subunit isoforms differ in voltage sensitivity and current kinetics
- categorised into TTX-sensitive and -insensitive groups
Alpha subunit
- large
- 4 non-identical domains in a single polypeptide chain
- 1 or 2 beta subunits can associate
Beta subunits
- 1 TMD, 1 extracellular N domain and 1 intracellular C domain
- beta 1+3 associate non-covalently with alpha
beta 2+4 associate covalently with alpha - modulate gating, expression, trafficking and pharmacology
The pore
- each domain similar to Kv subunit
- S5-S6 linked with pore loop
- P1 = selectivity filter
- P2 = charged acidic residue to attract sodium
- Lys(K) of DEKA motif is most critical for sodium selectivity
Activation gate
- below central cavity at S6 helix bundle crossing
- consists of often bulky hydrophobic residues to keep the region sterically constricted
- helix twisting at activation gate causes pore opening
S4 domains
- S4 domains sense depolarisation
- regularly spaced positive Arg/Lys are gating charges
- depolarisation makes inner leaflet of membrane more positive
- S4 moves up to activate
- acidic residues in S1-S3 keep the S4s ‘happy’ in the elevated position
Voltage-dependence
- electromechanical coupling = each VSD connected to pore domain via S4-S5 linker
- S4 of DI - DIII move almost synchronously
- correlate well with fast phase of gating current and Na current development
- S4 of DIV is lazy = movement correlates well with inactivation but not activation
Channelopathies
hyperactive Navs:
- epilepsy
- skeletal myopathies
- cardiac arrhythmias
- pain disorders
hypo- or inactive Navs:
- Brugada syndrome
- myotonias
- congenital insensitivity to pain
electrophysiological manifestations:
- abnormal peak Na current
- abnormal inactivation
- generation of abnormal current
Physiological phosphorylation
- NTs bind GPCRs
- Gs/Gq activate PKA/PKC
- decreased Nav current; changed inactivation
- decreased neuronal excitability
Pathophysiological phosphorylation
- PKA/PKA/MAPK/CaMKII/Tyr kinases/GSK3 etc.
- phosphorylate Nav in peripheral sensory neurones
- alter expression, trafficking, gating and inactivation
- sensitises nociceptive nerves
- nociceptive, inflammatory and neuropathic pain
Sodium currents
INa = N x Po x iNa
N = number of active Navs, governed by:
- trafficking
- expression level
- degradation
Po = open probability of a single Nav channel
- controlled by properties governing gating
iNa = current of a single Nav, governed by:
- electrochemical gradient
- permeabilities
- pore structure
Slow inactivation
- structure changes in pore/selectivity filter
- AP generation depends on how many Navs have fully returned to closed state
- slow inactivation keeps number of openable Navs higher for longer
- effect on trafficking to membrane
Fast inactivation
- essential for timely membrane repolarisation
- creates refractory period
- allows repetitive firing
IFM motif in DIII-DIV loop required for inactivation
- also sterically distorts the pore
- latches into a corner rather than plug blocking it
requires VS D4-S4 to move up
- late sodium current if doesn’t move up properly
- channel doesn’t inactive if doesn’t move up at all
- can be caused by channelopathies or toxins
