PCOL 2-1 Ligand Gated Ion Channels (LGICs)

Structural Features and Drug Interactions

• Pentameric superfamily receptors are characterized by their five subunit structure, which forms a central pore.
• Competitive antagonists of most GABA(A) receptors include Flumazenil, which reverses the effects of benzodiazepines.
• The drug Clonazepam enhances the actions of GABA and has a higher selectivity for specific receptors.
• Alcohol can act alone or enhance GABA’s actions but is less selective, increasing the risk of misuse and dangerous side effects.

GABA(A) Receptor Specifics

• Benzodiazepines selectively interact with the α1, α2, α3, and α5 subunits of GABA(A) receptors.
• Diazepam acts on all GABA(A) receptors, making it a broad-spectrum anxiolytic.
• The α2 subunit of GABA(A) receptors mediates anxiolytic effects when benzodiazepines are present.
• Effects of benzodiazepines can be eliminated using Flumazenil, a specific antagonist for benzodiazepine binding sites.

GABA and Its Enhancers

• The drug Thiopental binds to the transmembrane (TM) domain of GABA receptors and enhances GABA activity.
• High concentrations of Propofol directly stimulate GABA receptors.
• The drug Etomidate alters the pore conformation of the M2 segment in GABA receptors.
• The allosteric enhancer, Strychnine, enhances Glycine receptors (GlyRs).

Receptor Types and Their Mechanisms

• 5HT3R antagonists include Ondansetron, used to treat nausea.
• Linaclotide is specifically indicated for treating Irritable Bowel Syndrome (IBS).
• Voltage-dependent receptors can be blocked by Mg²⁺ ions, impacting their excitability.

NMDA and Excitatory Receptors

• Glycine acts as a co-agonist for NMDA receptor (NMDA-R) activation, necessary for channel opening.
• Excitatory Glutamate receptors (GluRs) consist of tetrameric structures with four subunits.
• Natural agonists for GluRs include glutamate and aspartate.
• Rigid receptor structures lead to increased selectivity for their respective ligands, enhancing pharmacological precision.

AMPA Receptor Structural Insights

• The GluR subunits contain a binding site for uncompetitive antagonists, specifically at the AMPA receptors (AMPA-R).
• The selectivity filter within the pore region of GluRs is located at the M2 helices.
• Selectivity in M2 helices is conferred by specific amino acids present in the sequence.
• Upon closure of the pore, the α-helices bend inward, maintaining structural integrity.
• When the pore opens, the helices undergo a conformational change, allowing ion flow and receptor activation.

Test your knowledge on pentameric superfamily receptors and excitatory ionotropic glutamate receptors with this quiz. Identify various receptors and their functions, including nAChR, 5-HT3 R, GlyR, GABAAR, AMPA, NMDA, Kainate, and ATP receptors. Explore the effects of endogenous ligands on ion channels.