Chapter 8: Synaptic Transmission and the Neuromuscular Junction PDF

# Chapter 8: Synaptic Transmission and the Neuromuscular Junction ## Learning Objectives The student should be able to: - Describe in detail the sequence of events that occur at a chemical synapse. - Describe the sequence of events that occur when acetylcholine binds to nicotinic or muscarinic rec...

# Chapter 8: Synaptic Transmission and the Neuromuscular Junction ## Learning Objectives The student should be able to: - Describe in detail the sequence of events that occur at a chemical synapse. - Describe the sequence of events that occur when acetylcholine binds to nicotinic or muscarinic receptors. - Describe how the ionic selectivity of the nicotinic ACh receptor channel was determined. - Outline the synthesis, recycling, and release of neurotransmitters. - Describe three different ways in which the action of a neurotransmitter at a synapse can be terminated. - Describe, giving examples, several mechanisms whereby drugs and diseases can affect the functioning of the neuromuscular junction. ## Key Terms - synapse - presynaptic neuron - postsynaptic neuron - synaptic transmission - neurotransmitter - electrical synapse - reciprocal synapse - synaptic cleft - presynaptic nerve terminal (bouton) - synaptic vesicles - ionotropic receptors - metabotropic receptors - nicotinic ACh receptor - muscarinic ACh receptor - motor unit - neuromuscular junction (end plate) - postjunctional folds - synaptic basal lamina - acetylcholinesterase (AChE) - choline acetyltransferase - active zones - end-plate potential (EPP) - excitatory postsynaptic potential (EPSP) - end-plate current - nonselective cation channel - inhibitory postsynaptic potential (IPSP) - miniature end-plate potential (MEPP) - nascent synaptic vesicles - fast axonal transport - dense-core secretory granules - clear synaptic vesicles - vacuolar-type H⁺ pump - neurotransmitter transport proteins - synaptobrevin - synaptotagmin - SNARE proteins - tetanus toxin - botulinum toxin - myasthenia gravis ## Synapses - RMP represents stored energy that can be used to generate electrical signaling within cells. - Cells must be able to signal between cells = intercellular communication. - The junction between two communicating cells is called a synapse. ### Types: - **Electrical synapses**: physical connections via gap junctions allowing electrical impulses to travel directly from cell to cell. - **Chemical synapses**: intercellular spaces (~30-50 nm) that require a neurotransmitter to traverse the space to signal the post-synaptic cell. ## SYNAPSES ### A: Electrical - This kind of synapse has low-resistance pathways that allow currents to flow directly between neurons. - Current flow through gap junctions electrically couples the neurons. - If current is injected into one neuron, the depolarization (or hyperpolarization) spreads to another electrically coupled neuron. - The depolarization of one cell produces a smaller depolarization of the adjacent cell. ### B: Chemical - In chemical synapses, released molecules of neurotransmitter carry the signal across the synaptic cleft. - Neurotransmitter is binding to ionotropic receptors on the postsynaptic cell to induce a depolarization known as a postsynaptic potential (PSP). ## Gap Junctions - create electrical synapses between adjacent cells by joining connexons. - allow unidirectional (rectifying synapses) or bidirectional (reciprocal synapses) movement of ions or small molecules between cells. ## Chemical Synapses - Chemical synapses are rectifying, propagating current from the presynaptic cell to the postsynaptic cell. - Neurotransmitters are packaged into vesicles using the energy of proton pumps. - An action potential arrives at the presynaptic axon terminal. - Depolarization opens voltage-gated Ca2+ channels and Ca2+ enters the presynaptic terminal. - The increase in intracellular [Ca2+] triggers fusion of synaptic vesicles with the membrane. Packets (quanta) of transmitter are released into the synaptic cleft. - Transmitters diffuse across the cleft and bind to specific receptors on the postsynaptic cell membrane. - Binding of the transmitter activates the receptor, activating the postsynaptic cell. - Termination of signal by (a) enzymatic destruction, (b) reuptake of transmitter into the presynaptic terminal or (c) diffusion of the transmitter away from the synapse. ## Nicotinic vs. Metabotropic - Neurotransmitters elicit postsynaptic signals through 2 possible mechanisms: - **Ionotropic Receptors:** ligand-gated channels that allow flux on ions and immediately (seconds) change membrane potential of the postsynaptic cell. - Example – Nicotinic ACh receptor at the neuromuscular junction - **Metabotropic receptors:** G protein coupled receptors eliciting downstream second messenger effector protein responses (seconds to minutes). - Example – Muscarinic ACh receptor in the parasympathetic nervous system. ## Synaptic Properties | | Electrical | Chemical | Ionotropic | Metabotropic | | ----------- | --------------- | ----------------- | ----------- | ------------ | | Agonist | None | e.g., ACh | e.g., ACh | e.g., ACh | | Membrane Proteins | 2 Connexons | Receptor/Channel | Receptor/Channel | Receptor/G Protein | | Transmission Speed | Instantaneous | ~1 ms delay | ~1 ms delay | Seconds to minutes | | Physical Distance | ~ 3 nm | ~ 30-50 nm | ~ 30-50 nm | ~ 30-50 nm | ## Neuromuscular Junction - The neuromuscular junction is a specialized synapse between motor neurons and skeletal myocytes (muscle fibres). - The whole assembly of muscle fibres innervated by the axon terminal from one motor neuron is called a motor unit. - The specialized synaptic region is called the neuromuscular junction or end plate. - The postsynaptic end plate membrane region of the myocyte has extensive invaginations called postjunctional folds, increasing target surface area. - The synaptic region is filled with an extracellular matrix meshwork mediating adhesion of the junction. - The matrix has a high concentration of acetylcholinesterase (AChE), which hydrolyzes ACh in the cleft for signal termination. ## End-Plate Potentials - ACh activates nicotinic receptors to elicit excitatory end-plate current. - The positive change in Vm of the muscle cell resulting from current influx is called the end-plate potential (EPP). - Activation of the nicotinic receptor opens a nonspecific monovalent cation channel, allowing flux of Na+ and K+. - Increase in Na+ conductance drives Vm transiently in the positive direction. - These EPPs are local end-plate graded potentials, which decay with distance away from the end-plate region. ## ACh Receptor - Each subunit of an ACh receptor is composed of 4 transmembrane regions, M1, M2, M3, M4, with extramembrane sequences above and below. ## Nicotinic ACh Receptors - The nicotinic cholinergic receptor binds two ACh molecules, opening a nonspecific monovalent cation channel. - Why do EPSPs dominate causing an EPP? More Na+ comes in than K+ leaving. ## Curare - Curare is an inhibitor to block ACh in NMJ - The decay of an end-plate potential is a graded (important) decay. ## Transmitter Synthesis and Recycling - Nascent synaptic vesicles are produced in the cell body of neurons and transported to the axon terminal by fast axonal transport using a microtubule system. - Vacuolar type H+ pumps create gradients across vesicle membranes to drive transmitter uptake into the vesicle for initial packaging and/or recycling. ## Transmitter Release - Transmitter release from the presynaptic cell occurs by Ca2+-dependent exocytosis. - Synaptobrevin (a v-SNARE) articulates with syntaxin and SNAP-25 (t-SNARE) on the axon terminal membrane forming a SNARE complex. - Synaptotagmin is the vesicle membrane Ca²+ sensor, which triggers membrane fusion and exocytosis of docked vesicles. - ATP-dependent processes dissociate the SNARE complex. ## Drugs Affect Synaptic Transmission - Tetanus and botulinum toxins (bacterial) block ACh release by interfering with SNARE complex formation. - Conotoxins (snail venom) block voltage-gated Ca2+ or Na+ channels on either membrane, interfering with synaptic transmission or AP initiation. - Tetrodotoxin (TTX) blocks voltage-gated Na+ channels. - Agonists or antagonists of the nicotinic receptor can interfere with appropriate ligand binding. - Acetylcholinesterase inhibitors prolong and magnify the EPP. ## Additional Notes - Depolar EPPs are only ionotropic/nicotine - End plate are graded - Don't confuse extracellular Ca2+ with intracellular Ca2+. - Important! - The image depicts a neuron and a muscle fibre with several labelled structures, including the synaptic cleft, the axon terminal, synaptic vesicles, and a muscle cell. The image also depicts several toxins that affect synaptic transmission and the channels they target. - The image also depicts the steps involved in the release of neurotransmitters, including the binding of neurotransmitter to receptors, the opening of ion channels, and the influx of ions into the postsynaptic cell.