4.5:
Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane receptors that open upon ligand binding and initiate cell signaling pathways. Many drugs target them for treating anxiety and insomnia.
These channels contain a ligand-binding site and a transmembrane pore for ion flow.
In the absence of a ligand, the channel remains closed. Ligand binding triggers a conformational change in the channel, opening the pore. The resulting influx of ions generates an action potential in the target cell.
When the ligand dissociates, the channel closes, preventing further ion movement.
Drugs target the ligand-binding or allosteric sites of ion channels and alter cellular responses by opening or closing the channel.
Some drugs bind at the ligand-binding site and mimic the effects of endogenous ligands by activating the receptor, while others block receptor activity. For example, varenicline treats smoking addiction by competitively inhibiting nicotine from binding its receptor.
Alternatively, drugs that bind allosteric sites on receptors allow or block the binding of the endogenous ligand. Sedatives like benzodiazepines bind GABA receptors and enhance their interactions with the inhibitory neurotransmitter GABA.
4.5:
Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of 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. Other ligand-gated ion channels, like the γ-aminobutyric acid (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 and limiting the nerve impulse conduction. It forms the basis of the sedative effects of anesthetic agents whose binding promotes calming and induces sleep.
Ligand-gated ion channels fall into three subfamilies:
- • The 'Cys-loop' subfamily includes nicotinic acetylcholine receptors, GABA, glycine, and 5-hydroxytryptamine receptors. These are pentameric receptors, and each subunit comprises four transmembrane α-helices. Both agonists and antagonists target neurotransmitter binding sites or allosteric sites to regulate the gating of these receptors.
- • The second subfamily is the 'Pore-loop' channels that include ionotropic glutamate receptors such as N-methyl D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors that bind the neurotransmitter glutamate. These tetrameric receptors have transmembrane loops instead of helices, forming an ion-conducting pore.
- • Lastly, the 'ATP-gated' P2X channels consist of cation-permeable ligand-gated ion channels that open on the binding of ATP. They are trimeric receptors having two transmembrane domains per subunit. They are vital in physiological processes like heart and skeletal muscle contraction and pain mediation.
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 neurotransmitter glutamate, stopping the influx of calcium ions and thereby preventing nerve damage due to prolonged cell excitability. The uncompetitive nature of this antagonist allows the site of communication between two nerve cells (the synapses) to activate during the physiological release of glutamate. This leads to improved cognition and can enable patients to carry out daily activities.