Synaptic Structure and Function

Synaptic Structure and Function

• Neurotransmitters are crucial for synaptic function, including their synthesis, release, and inactivation.
• Neurotransmitter receptor superfamilies include tyrosine kinase receptors, ionotropic receptors, and metabotropic receptors.

Synapse

• A synapse is a junction between two nerve cells, facilitating communication.
• A synapse has presynaptic and postsynaptic components.
• Different types of synapses exist, including axodendritic, axosomatic, and axoaxonic synapses.
• Presynaptic terminals contain synaptic vesicles filled with neurotransmitters.
• Astrocytic processes play a part in regulating synaptic function of the dendritic spine.

Neurotransmitters (Traditional Criteria)

• Pre-synaptic terminals have a store of the suspected transmitter.
• Effects of applying the suspected transmitter mimic effects of stimulating the pre-synaptic terminal.
• Substance binds to receptors on postsynaptic cell.
• Antagonist drug blocking receptors inhibits substance and pre-synaptic neuron effect.
• A mechanism must exist for neurotransmitter synthesis, including precursor and enzymes.
• A mechanism must exist for neurotransmitter inactivation (catabolic enzyme, active reuptake).

Important Notes

• Receptors determine the effect of a neurotransmitter depending on the specific receptor on each different neuron.
• Neuromodulators alter neurotransmitter function (e.g., synthesis, release, receptor interactions).
• One axon can release multiple neurotransmitters (coexistence or colocalization).
• Vertebrates and invertebrates often share the same neurotransmitters.

Table 6.1 (Substances Found to Have Neurotransmitter or Neuromodulatory Properties)

• Provides a list of substances with neurotransmitter/neuromodulatory properties, including various neurotransmitters and neuropeptides. Lists specific phenethylamines, indoleamines, cholinergics, amino acids, non-peptide hormones.

Neurotransmitters Synthesis

• Amino acids, monoamines, and acetylcholine are neurotransmitters with different synthesis pathways.
• Small, water-soluble molecules.
• Synthesized from dietary precursors, transformed into active compounds in the cell body or terminals, and packed into vesicles for subsequent release.
• Large molecule neuropeptides are synthesized in the cell body, packaged into vesicles, and transported to the nerve terminal.

Neurotransmitters Release - Exocytosis

• Release of neurotransmitters involves exocytosis from vesicles.
• Vesicles fuse with the presynaptic membrane, release neurotransmitter into the synaptic cleft.
• SNARE proteins are crucial in docking synaptic vesicles and mediating exocytosis.

Docking: SNARE proteins

• SNARE proteins are present in both presynaptic terminal membranes and synaptic vesicles.
• Entry of calcium into the presynaptic terminal activates SNARE proteins, which causes the synaptic vesicles to fuse with the presynaptic membrane, releasing neurotransmitter.

Botulinum (BOTOX)

• Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions. This results in paralysis.

Release of Neurotransmitters: Rate-controlling Factors

• Rate of cell firing (frequency) affects the amount of neurotransmitter released.
• Transport of precursors and enzymes influences neurotransmitter release rates.

Release of Neurotransmitters: Additional Rate controlling Factors

• Heteroreceptors respond to other neurotransmitters, while autoreceptors respond to the neurotransmitter released from the same neuron.

Release of Neurotransmitters: Receptor Types

• Axoaxonic synapses synapse on other cells, and somatodendritic are on cell body/dendrites.
• There are different receptor types: axoaxonic and somatodendritic.

Neurotransmitter Inactivation

• Enzymatic breakdown, reuptake, and uptake by glial cells inactivate neurotransmitters.
• A given neurotransmitter can undergo various inactivation processes.
• Psychoactive drugs often block reuptake mechanisms allowing the neurotransmitter to remain in the synaptic cleft.

Receptor Superfamilies

• Tyrosine kinase receptors are generally involved in neuronal growth during development and adulthood.
• Ionotropic receptors or ligand-gated channels operate at fast neuronal signaling with rapid desensitization.
• Metabotropic receptors or G protein-coupled receptors operate at longer latencies (milliseconds) for sustained signaling.

Tyrosine Kinase Receptors

• Activated by neurotrophic factors.
• Important for maintenance, survival and development of synapses.
• Includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 and 4.

Ionotropic Receptors (Ligand-gated ion channels)

• Large proteins with subunits, exhibiting heterogeneity in composition.
• Contain one or more neurotransmitter binding sites (orthosteric, allosteric).
• Operate at short latency (milliseconds) for fast neuronal signaling.
• Include nicotinic acetylcholine receptor, NMDA receptor, and GABA-A receptor.

Metabotropic Receptors (G protein-coupled receptors)

• Made of a single protein with seven transmembrane domains.
• Involved in sustained signaling and response that lasts longer than initial stimulation (minutes).
• G-protein can act on ion channels, or activate effector enzymes.

Structure of G proteins

• G-proteins are composed of three subunits (alpha, beta, gamma).
• Subunits can be divided into subfamilies and/or subtypes.
• Functioning is regulated via the binding of guanyl nucleotides (GTP/GDP).

Mechanism of Action

• Specific G proteins regulate effector enzymes and/or ion channels.
• Hydrolysis of GTP to GDP by the G alpha subunit inactivates the G protein.

Best characterized G proteins

• These proteins include Gs, Gi, Gq, Golf, Gt, and Go, which affect various second messenger pathways.
• Toxins (Cholera and Pertussis) can be utilized to study the structure and function of G proteins.

Direct interaction between G proteins and ion channels

• G proteins can directly interact with ion channels.
• K+ channels and IPSP are an example of this interaction.

Metabotropic Transmission (G protein-coupled receptor transmission)

• Occurs via a cascade of biochemical events that ultimately affect cellular functions.
• Second messengers are involved in these cascade.

Cyclic Nucleotides (cAMP/cGMP)

• Cyclic nucleotides are second messengers, implicated in various cellular processes.
• Different second messengers play crucial roles in biological functions.

Gene regulation by neurotransmitters in the brain

• Neurotransmitters alter gene expression via second messengers (cAMP) and transcription factors.
• cAMP-activated protein kinase phosphorylates transcription factors.

Immediate Early Genes

• These genes induce rapid but transient responses crucial for neuronal activation.
• Include products such as c-fos and c-jun.

Imaging brain activity (c-Fos response)

• Use of c-fos expression as a marker for neuronal activity in response to stimuli.
• Different brain regions show different levels of activity in response to stimuli.

Calcium and Calmodulin

• Calcium concentration plays a role in regulating protein activity in neurons.
• Calcium binds to calmodulin to influence various processes. Calcium/calmodulin-dependent protein kinases play an important role in neuronal signal transduction.

This lesson explores synaptic structure and function, emphasizing the role of neurotransmitters in synaptic communication. It covers neurotransmitter synthesis, release, inactivation, and receptor superfamilies. Also discussed are different types of synapses and the components involved in synaptic transmission.