Snapshot A 36-year-old male presents with ascending muscle weakness. The patient is generally healthy, with no pertinent past medical history. He states he recently recovered from diarrhea that has lasted over a week. Neurological examination is notable for weakness in the lower extremities and an abscence of patellar reflexes. (Botulinum toxin) Introduction Action Potential Overview initiation neuronal membrane potential becomes more positive → opening of voltage gated Na+ channels positive feedback loop threshold is reached → action potential generated propagation action potential generated at one portion of neuron → excitation of adjacent neuronal membrane signal thus propagates down the axon via opening of voltage gated Na+ channels neuromuscular junction when the propagated action potential reaches the presynaptic neuron, it becomes depolarized this opens voltage gated Ca2+ channels allows release of acetylcholine (ACh) from stored vesicles in the presynaptic neuron released ACh act on nicotinic receptors (a ligand-gated ion channel) on the motor end plate motor end plate depolarizes, and propagates the action potential down the muscle fiber, ultimately leading to muscle contraction Action Potential Initiation Initiation initial depolarization → opening of voltage gated Na+ channels increased Na+ inflow → opening of more voltage gated Na+ channels (positive feedback loop) threshold is eventually met → action potential generation clinical correlate tetrodotoxin (pufferfish consumption) binds fast voltage-gated Na+ channels in nerve tissue, which does not allow for depolarization or action potential formation can result in nausea, weakness, dizziness or can be fatal treatment is supportive Action Potential Propagation Propagation depolarized region of the neuronal membrane → excitation of adjacent neuronal membrane myelinated neurons Schwann cells myelinates axons of the peripheral nervous system (PNS) myelinates only 1 axon increases conduction velocity non-myelinated areas are called Nodes of Ranvier contains a high concentration of Na+ channels allows "jumping" of action potential from one Node of Ranvier to the next this is saltatory conduction clinical correlate Guillain-Barre syndrome autoimmune destruction of peripheral myelinated neurons classically associated with previous Campylobacter jejuni infection myelinated neuron examples sensory Pacinian corpuscles transmit vibrational sense and pressure via large, myelinated fibers non-myelinated neurons transmit potentials via Na+ channels that exist along the entire length of the axon (no Nodes of Ranvier) have same refractory period of Na+ channels as myelinated axons do but at a slower velocity of conduction due to lack of insulation (myelin) Neuromuscular Junction Neuromuscular junction propagated action potential reaches presynaptic neuron → opens voltage gated Ca2+ channels clinical correlate Lambert-Eaton syndrome autoantibodies against the presynaptic calcium channels → reduced ACh release → weakness associated with small cell carcinoma of the lung Ca2+ influx → ACh release with the help of SNARE proteins clinical correlate botulinum toxin cleaves SNARE proteins → decreased ACh release → flaccid paralysis tetanus toxin cleaves SNARE proteins → decrease release of inhibitory neurotransmitters (GABA and glycine) in the spinal cord → spasticity and overactivity released ACh act on nicotinic receptors (ligand gated ion channels) of the motor end plate clinical correlate myasthenia gravis autoantibodies bind the post-synaptic ACh receptor → weakness depolarization travels along the muscle cell via T-tubules, which are invaginations that allow for the skeletal muscle to be depolarized dihydropyridine receptors are then depolarized mechanically coupled to ryanodine receptors (Ca2+ release channels) on the sarcoplasmic reticulum increases intracellular Ca2+ concentration → binds to troponin C → cross bridge cycle See Skeletal and Cardiac Muscle Contractions topic clinical correlate malignant hyperthermia ryanodine or dihydropyridine receptor mutation → unregulated Ca2+ release into the muscle cytoplasm → sustained muscle contraction → increased aerobic metabolism → depletion of O2, ATP, and increased CO2 production and acidosis treatment: dantrolene