Ion Channels and Synaptic Transmission

• Ion channels feature hydrophilic amino acids on extracellular and intracellular loops.
• Hydrophobic amino acids are located in transmembrane domains.
• Ion channels consist of 4 to 6 subunits, with each generally having 4–6 transmembrane domains.
• Selective permeability is determined by pore size, charge of amino acids lining the pore, and hydration shell stripping.
• Voltage-gated channels respond to changes in membrane potential.
• Ligand-gated channels open when specific neurotransmitters or molecules bind.
• Mechanosensitive channels respond to mechanical forces.
• Temperature-sensitive channels open in response to heat or cold.

Synaptic Transmission

• When an action potential reaches the axon terminal, voltage-gated Ca²⁺ channels open.
• Calcium influx triggers vesicle fusion with the membrane.
• Neurotransmitters (NTs) are released into the synaptic cleft.
• Vesicles are docked and primed at the active zone near voltage-gated Ca²⁺ channels.
• NT release from vesicles is described as a quantal distribution.
• Quantal content is the number of vesicles released per action potential affecting Ca²⁺ influx, vesicle availability, and presynaptic mechanisms.
• Quantal size is about the amount of neurotransmitter per vesicle determined by vesicle storage capacity and transmitter concentration.
• Synapses become depressed because of a decrease in NT release due to vesicle depletion or receptor desensitization.
• Synapses become facilitated because of an Increase in NT release due to residual Ca²⁺ accumulation.
• Vesicle movement occurs in 6 steps: synthesis, transport, docking, priming, fusion/release, and endocytosis/recycling.
• Proteins involved in vesicle cycling include: Rab3 and Rim (transport & docking), Munc13 and Munc18 (priming), SNARE complex (Synaptobrevin, Syntaxin, SNAP-25) and Synaptotagmin (fusion & release), and Clathrin and Dynamin (endocytosis).
• The three vesicle pools are: Readily Releasable Pool (RRP), Recycling Pool, and Reserve Pool.
• RRP vesicles are docked and primed for release.
• Recycling Pool vesicles are near active zones, replenishing RRP.
• Reserve Pool vesicles are farther from the membrane, mobilized under high activity.

Neurotransmitters

• Classical neurotransmitters include Acetylcholine (ACh), Glutamate, GABA, Glycine, Dopamine, Serotonin, Norepinephrine, Histamine.
• Non-Classical neurotransmitters include Neuropeptides, Gasotransmitters (NO, CO), and Endocannabinoids.
• Classical NTs are stored in vesicles and released by exocytosis, acting on synaptic receptors. Non classical neurotransmitters break this rule.
• Gases (NO, CO) diffuse freely.
• Neuropeptides require high-frequency firing.
• Endocannabinoids work retrogradely.
• The 5 stages of a neurotransmitter’s life are: synthesis, packaging, release, receptor binding, and degradation or reuptake.
• Enzymes involved in neurotransmitter life cycle: Choline Acetyltransferase (ChAT) and Acetylcholinesterase (AChE) for Acetylcholine, Tyrosine Hydroxylase (TH) and Monoamine Oxidase (MAO) for Catecholamines, Tryptophan Hydroxylase (TPH) for Serotonin, and Glutamate Decarboxylase (GAD) for GABA.

Neurotransmitter Receptors

• Ionotropic receptors are ligand-gated ion channels with a fast response.
• Metabotropic receptors (GPCRs) are slow, signaling through second messengers.
• The reversal potential is the membrane voltage where no net current flows.
• Ion movement depends on the difference between the membrane potential and the reversal potential.
• Excitatory ions are Na⁺, Ca²⁺ (Depolarization).
• Inhibitory ions are Cl⁻, K⁺ (Hyperpolarization).
• GPCRs are slow to activate G proteins, which trigger intracellular cascades.
• GPCR inactivation involves GPCR kinases (GRKs) phosphorylating the receptor and Arrestins binding to prevent further signaling.

Intracellular Signaling

• Neuromodulation alters neuronal excitability via intracellular pathways.
• The 4 G-alpha subunit types are: Gαs, Gαi/o, Gαq/11, and Gα12/13.
• Gαs stimulates cAMP production.
• Gαi/o inhibits cAMP production.
• Gαq/11 activates phospholipase C (PLC).
• Gα12/13 regulates cytoskeleton via RhoA.
• cAMP activates PKA.
• cGMP activates PKG.
• IP3 releases Ca²⁺ from stores.
• Ca²⁺ triggers multiple pathways.

Electrical Synapses

• Electrical synapses are faster, bidirectional, and have no synaptic delay.
• Gap junctions are made of connexins, forming connexons.
• Homomeric gap junctions have identical connexins.
• Heteromeric gap junctions have mixed connexins.
• Consequences of gap junction activity include synchronization of neural activity and increased electrical conductance.
• Not all signals propagate equally due to voltage drop, affecting signal strength. Coupling ratios allow for the measurement of this activity.