Ligand-Gated Ion Channels Quiz

Ligand-Gated Ion Channels - Cys-Loop Receptors

• Cys-loop receptors include nicotinic acetylcholine receptors, 5-HT3 receptors, GABA-A receptors, strychnine-sensitive glycine receptor, and zinc-activated channel (ZAC).
• Ionotropic glutamate receptors include NMDA receptors, AMPA, and kainate receptors.
• P2X receptors are also part of this group.
• Learning outcomes include discussing receptor structure, cellular and physiological function, and drug action at various receptors.
• Key terms include receptor, a class of cellular macromolecules that directly deals with chemical signaling. Ligand, a substance bound to a protein and is used in pharmacology. Affinity, is the tendency of a ligand to bind to its receptor. Agonist, a ligand that binds to a receptor and alters the receptor's state, resulting in biological responses. Antagonist, A drug that reduces the action of another substance, usually an agonist, may act at the same receptor. Channel blocker, molecule or ion that binds to the pore of an ion channel and prevents the flow of ions. Protein subunit, a single protein molecule assembling with others to form an oligomer. Oligomer, protein macromolecule formed from two or more protein subunits.
• Cys-loop receptors have a pentameric structure, meaning they are composed of five protein subunits.
• Subunit composition significantly impacts pharmacology.
• Each receptor subunit has an extracellular N-terminus, large intracellular loop, small intracellular loop, four hydrophobic transmembrane domains, and a small extracellular loop and extracellular C-terminus.
• The ligand binding site in the nicotinic acetylcholine receptor is located between the subunit interfaces.
• The arrangement of transmembrane domains surrounding the channel pore is evident in receptor structures.

Nicotinic Acetylcholine Receptors

• Permeable to Na+, K+, and Ca2+.
• Nonspecific cation channels.
• Modulate fast synaptic excitation.
• John Newport Langley (1852-1925) investigated the effects of nicotine and curare on denervated skeletal muscle.

Myasthenia Gravis

• Skeletal muscle autoimmune disorder from loss of nAChRs at the neuromuscular junction.
• Symptoms include muscle weakness and fatigue, especially facial and eye muscles.
• More common in women under 40 and men over 60.
• Diagnosis can be challenging.
• Diagnosis methods include blood tests for antibodies to nAChRs, edrophonium tests, and single-fiber electromyography.

Myasthenia Gravis - Pharmacotherapy

• Neostigmine (Prostigmin®), Pyridostigmine, and Edrophonium are reversible competitive antagonists of AChE with differing durations of action.
• Corticosteroids are immunosuppressants, inhibiting cytokine and TNF gene expression.

Congenital Myasthenic Syndrome (CMS)

• Mutations affecting nACh receptor expression/kinetics/agonist binding/and channel gating.
• May be presynaptic (ACh) or postsynaptic (AChRs, fast/slow channel CMS).
• Various mutations can affect presynaptic ACh vesicular transport, acetylcholinesterase activity, and postsynaptic ACh receptor expression.

5-HT₃ Receptors

• Permeable to Na+, K+, and Ca2+.
• Nonspecific cation channels.
• Modulate fast synaptic excitation.
• Important drug targets for antiemetic effects.
• Examples include ondansetron, granisetron, tropisetron, dolasetron, and palonosetron.
• Alosetron is a 5-HT3 antagonist used in the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS) in women.

GABA Receptors

• GABA receptors are a target for positive allosteric modulators, including anaesthetics, hypnotics, and neurosteroids.
• Propofol, thiopental, and etomidate are examples of intravenously administered anesthetics.
• Benzodiazepines are positive allosteric modulators.
• Examples include Diazepam, Alprazolam, Clonazepam, Lorazepam, etc.
• Neurosteroids can directly activate the GABA receptor high concentrations or during specific conditions.
• Key anaesthetics are positive allosteric modulators of GABA receptors.
• Non-benzodiazepine hypnotics are positive allosteric modulators that act at the benzodiazepine binding site on the synaptic GABA receptor.
• Zolpidem, Zopcilone, and Zaleplon are used to treat insomnia.

Neurosteroids and GABA Function

• Neurosteroid levels change due to pregnancy, stress, aging, and substances like alcohol and SSRIs.
• Postnatal depression, premenstrual tension, epilepsy may be due to variations in pregnane steroid levels in the brain.

Phasic and Tonic Conductance

• Phasic conductance is mediated by postsynaptic receptors activated during synaptic GABA release.
• Tonic conductance is mediated by extrasynaptic receptors by ambient GABA concentrations.
• This tonic current can be influenced by neuronal excitability.
• Tonic current is also potentiated by neurosteroid concentrations.

Drugs that Act as Agonists at Nicotinic Acetylcholine Receptors (nAChRs)

• Acetylcholine: a full agonist at both nAChRs and mAChRs. Used in cataract surgery.
• Nicotine: a full agonist at nAChRs. Used for smoking cessation. Nicotine delivery via controlled release.
• Varenicline: inhibits nicotine binding to the α4β2 nAChR, a partial agonist, easing nicotine withdrawal symptoms.