Ligand Gated Ion Channels Flashcards
Mechanism of Ligand Gating
Open probability changes with the binding of a ligand to its othosteric site. Examples of LG ion channels are Ach (nicotinic acetylcholine receptor, cation non spelective) and P2X (cation selective, binding of ATP leads to incr Ca2+)
Can be mediated by other channels and protein-protein interactions.
Like VG channels, they respectively lead to a change in Po with signalling pathways and protein interactions from action potentials fired and neurotransmitters release (Kir, CFTR) and can also signal the opening of VG channels (eg. Ach opening Cav channels)
Functional roles of ligand gated ion channels
- Fast chemical synapses> excitatory and inhibitory
- Nociception
- Mechanosensation
- Autocrine and paracrine signalling
- Mostly in exciteable cells, some epithelial cells.
Receptors
- Glycine receptor (GlyR) - Cl- channel, binding of Glycine. Has 3 alpha subunits and 2 beta subunits.
- y-aminobuteric acid receptor (GABAAR) - Cl- channel
+Nernst pot of Cl- is negative > if open up channels, leads to hyperpolarise in negative direction. In neurons in CNS system, these two channels inhibit CNS through moving membrane potential away from the threshold value for an AP.
Ionotropuc Glutamate receptors (GluR) activated by Glutamate.
+ Kainate, AMPA and NMDA can also activate specific glutamate
+ Cation selective channels > Excitatory, causes a depolarisation. Reversal potential is at 0, when activated they move membrane potential closer to the threshold value
Glutamate response
EPSP Excitatory Post synaptic Potential
- Vm is nevative to the nernst of Cation
- Movement of cation inwards, inward cation current = inwards EPSC
Glycine response
IPSP Inhibitory Post Synaptic Potential
- Vm is more positive to nernst of Chloride
- Inward Cl-, outward IPSC
+ Negative current moves in which generates an outwards current.
GlyR in experiments
+Experimentally, in glycine receptors dont use physiological conditions, as its difficult to measure at normal chloride levels > equal conc. used IC and EC to sit the nernst potential at 0.
+ Therefore, incorrect Vm of Cl- in experiments > some inward currents in physiological conditions would be outward currents.
Hyperekplexia
Autosomal dominant AND recessive forms ? impacts how GlyR behaves
INFANTS:
- Hypertonia
- Increased risk of SIDS
- Enhanced startle reflex > response is not suppressed by inhibitory pathways, enhanced activation > Auditory and tactile stimuli
- Apnoea
- Life threatening > increased death rate
ADULTS:
- Hypertonia disappears
- Enhanced startle reflex remains
- Falls and injuries prone due to reflex response
- Not life threatening anymore > does depend on injuries caused
CAUSE:
- Enhancement of motor response, but physiology of response is normal (latency, onset of EMG)
- Defect in gain and modulation > amount of reflex response regulation
- Benzodiazepine treatment > activated GABAA > targetting a different Cl- channel to alleviate symptoms.
Mutations in the GlyR
GLRA1 - alpha GlyR
- Lysine 276 glutamic acid (dominant)
- Log dose - responsive curve: increase in EC50 glycine results in decreased Imax
- A384P mutation > glycine sensitivity isn’t always impacted
- Proline 250 threonine (dominant)
