Voltage-gated Potassium Channels

Voltage-gated Potassium Channels

1. Function

   • crucial regulators of excitability
     • Conductance and cell time-constants
     • Set firing properties (such as how many spikes) and action potential threshold
     • Action potential time-course (duration)
       • Increasing K channel conductance shortans AP length
       • Decreasing K Channel conductance lengthens AP
   • Would not work without Sodium channels and the Na/K ATPase Pump

2. Neuronal Excitation and Ion Concentrations

   • Resting potential
     • around -60 mV
   • Action potential (Depolarisation)
     • Threshold potential up to around +45mV
     • AP shape depends on Na+ K+ balance
   • Refractory Period
     • Hyperpolarisation
       • mV below resting potential
     • Repolarisation
       • point where mV begins to drop after action potential
     • No further excitation, even at increasing intensities of stimuli
   • Ion concentrations
     • Intracellular
       • Extracellular
         • K+ 4.5mM
           • Na+ 145mM
             • Ca2+ 1.2mM
               • Cl- 116mM
       • K+ 120 mM
         • Na+ 15mM
           • Ca2+ 0.0001mM
             • Cl- 20mM
   • Antagonists
     • TEA
       • will block most K+ channels at 10-100mM, but at 1 mM it is relatively specific for Kv3 (and BK channels)
     • Dtx
       • specifically blocks Kv1 channels
   • • Kv1 Active at Depolarisation. Increased conductance in Kv1 will increase threshold potential. Kv3 active at peak mV and during repolarisation. Increase conductance shortens AP
   • Reversal Potential
     • -88mV
       • +60mV
         • +130mV
           • -61mV

3. K+ Channel Families

   • Leak Channels
     • 2 Families
       • Inward Rectifiers
         • 2 Transmembrane domains
         • Oldest in evolutionary terms
           • then elaborated upon
         • e.g. KcsA
       • Tandem pore, outward rectifiers
         • 4 TM
         • KCNK channel family
           • subject to strict regulation by second messenger systems
     • Set resting membrane potential
   • Gated channeld
     • Ligand-gated
       • 3 Families
     • Voltage Gated
       • 3 Famlies
         • Kv1-Kv4
           • Delayed Rectifiers
         • Kv5-Kv9
           • Accessory subunits
         • Kv10-Kv12
           • Heart
       • Repolarizing AP and controlling excitability
       • Most recent in evolution
     • 6 TM

4. Kv Channel Structure

   • Homotetramer
     • Kva and KvB subunits
       • four alpha-subunits, which span the cell membrane
       • four beta-subunits that lie just inside the membrane
   • Kva
     • 6 transmembrane alpha helices
       • TM regions 1-4 form the voltage-sensing region
         • TM 4 has has positively charged residues of arginines and lysines to detect transmembrane voltage changes
     • Selectivity sequence
       • TVGYG
       • Allows K+ conductance only
     • Tetramerisation occurs at N-terminal
     • C-terminal used in phosphorylation and regulation
     • N-Terminal domain acts as a 'ball and chain' plug in inactivation
       • For inactivation to occur, a positively charged inactivation particle (ball) has to pass through one of the lateral windows and bind in the hydrophobic binding pocket of the pore's central cavity. This blocks the flow of potassium ions through the pore. There are four balls and chains to each channel, but only one is needed for inactivation.

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