Neurotransmitters and Receptors Overview

Neurotransmitters and Receptors

• Neurotransmitters (NTs) and neuromodulators are covered in Ganong's Review of Medical Physiology, chapter 7; Basic & Clinical Pharmacology (chapters 21 & 23), 15th ed. by Katzung; Foye's Principles of Medicinal Chemistry (chapters 6 & 8), 8th ed.; and Goodman & Gilman's: Pharmacological Basis of Therapeutics (chapters 14 & 23), 13th ed.
• Lecture objectives include describing neuronal structure, NT/neuropeptide synthesis, excitatory/inhibitory neuronal transmission, NT classes and their effects, catecholamine/acetylcholine synthesis/metabolism, the five steps of neuronal signal transmission, and the effects of pharmacological agents on neuronal signaling.
• Ion channels (voltage-gated and ligand-gated [ionotropic]) and metabotropic receptors (GPCRs) regulate neurotransmitter effects.

Ion Channels/Neurotransmitter Receptors

• Voltage-gated ion channels (A): Control ion flow across cell membranes in response to voltage changes.
• Ligand-gated ion channels (ionotropic) (B): Open or close in response to the binding of a neurotransmitter.
• Metabotropic receptors (GPCRs) (C): Activate intracellular signaling pathways upon neurotransmitter binding.
  • Alpha subunits activate downstream effectors.
  • Beta/gamma subunits directly modulate ion channels.
• Membrane-delimited regulation of ion channels occurs through metabotropic receptors.
• Second messengers regulate ion channels via receptors.

Ion Flux/Ion Channel Regulation

• Depolarization (neuronal activation): Influx of sodium (Na+) and/or calcium (Ca2+).
• Hyperpolarization (neuronal inhibition): Influx of chloride (Cl-) and/or efflux of potassium (K+).

NT Release, Action, and Reuptake

• Action potential (AP) triggers voltage-gated calcium (Ca2+) channels to open, causing neurotransmitter (NT) release into the synaptic cleft.
• NTs bind to receptors on the postsynaptic membrane, causing a change in the neuron's membrane potential.
• NTs are removed from the synapse via reuptake or enzymatic breakdown.

Action Potentials/Excitatory and Inhibitory Signals

• Simultaneous activation of excitatory synapses can lead to enough depolarization to generate an action potential (AP).
• Integration of excitation and inhibition involves excitatory postsynaptic potentials (EPSPs), and inhibitory postsynaptic potentials (IPSPs) which can prevent an excitatory potential from reaching a threshold to stimulate depolarization.

Specific Neurotransmitters & Receptors

• Acetylcholine (ACh): Synthesized from choline and acetyl CoA; metabolized by acetylcholinesterase (AChE); receptors include muscarinic (GPCRs) and nicotinic (ligand-gated Na+ channels).
  • Muscarinic receptors (M1, M3, M5): Excitatory.
  • Muscarinic receptors (M2, M4): Inhibitory.
• Dopamine: Catecholamine synthesized from tyrosine, metabolized by MAO and/or COMT; D1 & D5 are excitatory, D2-D4 are inhibitory.
• Norepinephrine (NE): Catecholamine synthesized from tyrosine; metabolized by MAO and/or COMT; alpha1, beta1, and beta2 are excitatory; alpha2 is inhibitory.
• Glutamate: Major excitatory neurotransmitter synthesized from glutamine. Receptors include inotropic AMPA/kainate and NMDA receptors, and metabotropic mGluR1-5.
• GABA: Major inhibitory neurotransmitter synthesized from glutamate; metabolized by GABA-transaminase. Receptors include inotropic GABA-A (chloride [Cl-] channel) and metabotropic GABAB receptors.
• Serotonin: Synthesized from tryptophan; metabolized by MAO; receptors include inotropic 5-HT3 receptors and metabotropic 5-HT1A/5-HT2a receptors.

Drug Targets in Neurological Conditions

• Drug targets include neurotransmitter synthesis, packaging, calcium channels, receptors, reuptake transporters, metabolism, release, and action potential modulation.
• Specific drugs covered.

GABA-A Receptor

• Ligand-gated chloride (Cl-) channel; activation results in hyperpolarization, inhibiting nerve signal transmission.
• Pentameric structure with two alpha subunits (six isoforms), and differing binding characteristics and effects.
• Benzodiazepines, barbiturates and z-drugs are allosteric modulators of GABA-A receptor that enhances GABA binding and extends the duration of Cl- channel opening.

Benzodiazepines

• General anxiolytics, sedatives, hypnotics; bind to a site distinct from GABA and enhance GABA binding and increase duration/frequency of chloride channels.
  • Metabolism mainly via CYP3A4 and UGT1 glucuronidation, with exceptions for lorazepam, oxazepam, and temazepam.
  • Renal elimination is the major pathway for elimination.

Drugs in Neuro Section

• Drugs covered in the neuro section include various sedatives, hypnotics, anxiolytics, pain medications and other miscellaneous groups.

Clinical Uses

• Sedatives/hypnotics are used for insomnia, anxiety, alcohol withdrawal, medical/surgical procedures, trauma-induced coma, cancer-related sedation, epilepsy, and depression.

Flumazenil

• Competitive GABA-A receptor antagonist (BDZ antagonist), used as an antidote for high benzodiazepine overdose, short half-life, and rapid onset that is used to treat benzodiazepine overdose.