Ion channels + channelopathies

Voltage-gated ion channel structure

4 domains, each with 6 alpha helices. S1-4 voltage sensory, S5 and 6 with p-loop form pore. Domains 3 to 4 has inactivation gate.

Patch clamp electrophysiology

Records changes in membrane potential by clamping section of membrane inside electrode, and then stimulating using electrode.

Other methods of studying channels

Site-directed mutagenesis, molecular dynamic modelling, cryo-electron microscopy (freeze and crystallise proteins, use X-ray crystallography to image, reconstruct using computer)

Dravet syndrome

mutation in Nav1.1, expressed in GABAergic neurons. blocks channels, so GABA released less. seizures.

Small fibre neuropathy

gain of function mutation in Nav1.7, expressed in nociceptive neurons. Will be stimulated at lower threshold, causing more frequent APs in C and A delta fibres.

Ligand activation vs voltage

Instead of voltage-sensing region, receptor region causes opening after ligand binding

Ligand-gated structure (nicotinic acetylcholine)

5 identical subunits, each with M1-M4 alpha helices, and structures contributing to receptor region.

nicotinic acetylcholine receptor function

Found at neuromuscular junctions. Release of acetylcholine from nerve innervating muscle fibre. Binds to receptors on post-synaptic membrane, causing depolarisation. 

Superfamily of ligand-gated channels

Glycine, GABA, glutamate. All share 4 alpha helices in subunits, and similar receptor binding regions. All key neuromodulators in CNS.

Myasthenia gravis

Autoimmune - anti-acetylcholine receptor antibodies attack these receptors. Means more acetylcholine required to generate same muscle response - causes progressive muscle weakness, as acetylcholine is depleted throughout day.

Limbic encephalitis

Autoimmune - glutamate receptors. Causes psychosis, seizures (overexcitability)