14.3 : Ligand-gated Ion Channels

Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.

Three Subfamilies of Ligand-gated Ion Channels

Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that include the ionotropic glutamate receptors such as the N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the kainate receptors that bind the neurotransmitter glutamate. Lastly, the 'ATP-gated P2X channels' consist of cation-permeable ligand-gated ion channels that open on the binding of ATP and play a vital role in various physiological processes like heart and skeletal muscle contraction, mediation of pain, etc.

Ligand-gated ion channels play a vital role in intercellular communication in the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. While some ligand-gated ion channels, like the GABA receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell lowers the membrane potential, i.e. hyperpolarizes the membrane, thereby inhibiting the firing of new action potentials, limiting the propagating effects of the cell. This forms the basis of the sedative effects of anesthetic agents whose binding promotes calming and induces sleep.

Clinical Relevance

In the case of Alzheimer's disease, the treatment that involves cholinesterase inhibitors prevents the breakdown of the neurotransmitter acetylcholine and prolongs its circulation, helping to improve cognitive functions. Treatment with glutamate receptor antagonists, like memantine, helps manage the memory loss and brain damage associated with the disease. Here, the antagonist binds to the ligand site of the actual neurotransmitter glutamate, stopping the influx of calcium ions, thereby preventing nerve damage due to prolonged excitability of the cell. The uncompetitive nature of this antagonist allows for the activation of the synapse, the site of communication between two nerve cells, during the physiological release of the glutamate, helping in the symptomatic improvement of the patients to carry out daily activities.