Ligand gated ion channels

Ligand gated ion channels definition

integral membrane proteins that contain a pore which allows regulated flow of selected ions and a receptor for binding of an agonist

2 different types of ligand gated channels

• Excitatory (pass (+) ions like sodium, potassium, calcium)

  • nicotinic acetylcholine

  • seratonin

  • ionotropic glutamate

    • AMPA, NMDA, Kainate

• Inhibitory (pass (-) ions like chloride)

  • GABA(A)

  • Glycine

List examples of ligand gated ion channels and the ion selectivity of the channel (image)

List the three different types of receptors

• Cys-loop receptor (nicotinic ACh) superfamily

• Glutamate receptor family

• P2X receptor family

Cys-loop receptor (nicotinic ACh) superfamily

• pentamer

  • nicotinic ACh receptors

  • 5-HT3 receptors

  • GABA(A) receptors

  • ZAC

Glutamate receptor family

• tetramer

  • NMDA receptors

  • AMPA receptos

  • Kainate receptors

P2X receptor family

• trimer

  • P2X receptors

AMPA Receptors

• part of the glutamate receptor family

• mediator of fast excitory synaptic transmission

• permeabile to sodium, potassium, calcium

• 4 subunits consisting of 2 dimers

NMDA receptors

• ionotropic glutamate receptor

• permeable to sodium, potassium, calcium

• critical for synaptic plasticity, learning, and memory

• involved in nic addiction and ischemic stroke

GABA(A) Receptor

• part of the Cys-loop receptor (nicotinic ACh) superfamily

• inhibitory receptor

• permeable to chloride ions - results in hyperpoarization of the membrane and inhibits neuron depolarization

• interacts with G-coupled receptors - dopamine D5

Gating mechanisms (3)

• Activation (binding of agonist)

  • transition of channels from closed to open states

• Deactivation (removal of agonist)

  • transition of channels from open to closed states

• Desenitization

  • fraction of channels in an open state in the maintained presence of an agonist

  • non-conducing states - do not respond to activating stimuli

Describe the use of blocking agents to understand gating of ion channels

• channel blockers are used as analytical probes in studies of channel gating

• most channel blockers enter and bind to the channel in an open state

• use dependent

  • requires activation of the channel

• channel blocker unbinding - depends on gating transitions

  • blocker may become trapped in the channel

• “foot in the door” channel blockers physically occlude closure of the channel gate

Describe potential clinical application of ligand gated ion channels

LGIC interactions for Neuroprotection

• glutamate receptors have critical roles in brain functions

• interactions between ionic glutamate receptors and other proteins could lead to potential therapuetic

  • AMPA activation increases the formation of GluR2-GAPDH complex and promotes cellula internalization - blocking formation of this complex protects cells against glutamatergic excitoxicity and ischemia induced neural damage

  • interaction between NMDA NR2 subunit and PSD95 cuases nitric oxide neurotoxicity - blocking this interaction could protect neurons from excitoxicity and ischemic brain damage