Ligand Gated Ion Channel

Nicotinic Acetylcholine Receptor (nAChR) Action

When ACh binds to its binding site, conformational change increases the probability of opening the channel.

Muscle nAchR subunit composition (Adult)

2x α-subunit, β, ε, and δ subunits; localized to the endplate.

nAChR Cation Conductance

Generally a non-selective cation channel; Na+ conductance is 10^7 ions/channel/sec; Ca++ conductance increases with α3/α5 and is largest with α7.

High Affinity ACh Binding Site Width

Approximately 10 nM.

Low Affinity ACh Binding Site width

Approximately 1 μM.

Nicotinic Agonist Examples

ACh, Nicotine (Varenicline @ α4β2), Carbachol, Succinylcholine.

α-bungarotoxin mechanism

Irreversibly binds to and blocks the nAChR, producing neuromuscular blockade and skeletal muscle paralysis.

β-bungarotoxin mechanism

Prevents the release of ACh from motor nerve endings. Nondepolarizing Neuromuscular Blocking Agents (NMBA)

Depolarizing Neuromuscular Blocking Agents (NMBA)

Drugs (like Succinylcholine) that produce initial activation (Phase I, transient twitching/fasciculations) followed by a blockade due to sensitization/unresponsiveness (Phase II, flaccid paralysis).

Succinylcholine

A Depolarizing Blocking Drug; an agonist composed of two molecules of ACh coupled together.

d-Tubocurarine (Curare) use

NON-depolarizing block; first agent used as a muscle relaxant in general anesthesia (1940s).

GABAa Receptor Action

GABA binding causes the channel to open, allowing chloride (Cl-) to enter the cell, causing hyperpolarization (cell becomes more negative).

GABAa Receptor Allosteric Modulators

Bind to several different sites on the receptor; Benzodiazepine (BZD) Agonists, Inverse Agonists, and Antagonists exist.

Benzodiazepine (BZD) Agonist Mechanism

Positive Allosteric Modulation (PAM); increases the frequency of channel opening and increases the affinity/potency of GABA for the GABAA receptor.

Example BZD Agonists (PAMs)

Diazepam (Valium), Librium®, Ativan®.

BZD Inverse Agonist Mechanism

Negative Allosteric Modulation (NAM); reduces the influx of Cl- below the baseline state (anxiogenic effect).

Example BZD Inverse Agonist (NAM)

Ro 15-4513.

BZD Antagonist Example

Flumazenil (used for treatment of OD).

GABAA receptor subunit responsible for sedation

α1 containing R subtypes.

Zolpidem (Ambien CR) target

A non-BZD structure acting as an agonist at the BZD site, selective for α1 containing GABAA R (leading to sedation).

Neurosteroid Modulators (PAMs) for GABAA

Agents like Brexanolone (allopregnanolone) and Zuranolone (next generation neurosteroid); increase GABA functioning in the brain. Brexanolone/Zuranolone mechanism

Glutamate Receptors (iGluR) Subtypes

NMDA, AMPA, and KAINATE.

Glutamate Receptor Cation Selectivity

Na+, K+, Ca2+; NMDA receptors are most permeable to Ca 2+.

NMDA Receptor Antagonist Examples

PCP, Ketamine (Hallucinogen/Dissociative anesthetic), and Memantine (used for Alzheimer’s disease).

Renal Transport Drug Target Families

SLC12 (NKCC, NCC) and SLC5 (SGLT).

NKCC2 transporter

Na+ - K+ - 2Cl- transporter (SLC12A1); expressed in the kidney (Thick Ascending Limb, TAL); responsible for 25% of Na load reabsorbed.

Loop Diuretics (e.g., Furosemide, Torasemide)

Inhibit the Na-K-2-chloride cotransporter (NKCC2) at the TAL; high efficacy (20-30% of Na+ reabsorption).

NCC transporter

Na+ - Cl- cotransporter (SLC12A3); electroneutral @ apical membrane of the Distal Convoluted Tubule (DCT); responsible for 5% Na reabsorption.

Thiazide Diuretics (e.g., Hydrochlorothiazide)

Inhibit Na+ reabsorption via blocking the Na/Cl- cotransporter (NCC) in the DCT; moderate efficacy (5-10% of filtered load).

SGLT2 transporter

Sodium-Glucose Co-transporter (SLC5A1) symporter on the luminal surface of the Proximal Convoluted Tubule (PCT); reabsorbs 90% of glucose.

Empagliflozin (SGLT2 Inhibitor)

Inhibits SGLT2, reducing 30-50% of glucose reabsorption; used to help manage Type 2 Diabetes (T2D).

SLC6 Neurotransmitter Transporter Family

Sodium- and chloride-dependent transporters involved in major depression, anxiety disorders, ADHD, and obesity treatment.

Key SLC6 Neurotransmitter Transporters

Norepinephrine (NET SLC6A2), Dopamine (DAT SLC6A3), Serotonin (SERT SLC6A4).

Cocaine mechanism

A non-transportable inhibitor of DAT, SERT, and NET fairly equally; DAT inhibition is responsible for its rewarding effects.

Amphetamine/Methamphetamine mechanism

Promote reversal of DAT/SERT/NET direction, leading to competitive inhibition of uptake and depletion of neurotransmitter in the pre-synaptic cell.

SSRI (Selective Serotonin Reuptake Inhibitor) mechanism

Inhibits the SERT (SLC6A4) transporter, leading to increased extracellular serotonin levels; used for depression, anxiety, OCD.

Example SSRIs

Fluoxetine (Prozac), Sertraline (Zoloft), Escitalopram.

Drugs that act as Use Dependent Blockers

Lidocaine and DHPs (Dihydropyridines).