Acetylcholine
A neurotransmitter critical for muscle activation, memory, and cognitive function. Acetylcholine signalling at the neuromuscular junction is disrupted in myasthenia gravis (treated by zilucoplan). Acetylcholine deficiency in the brain is associated with Alzheimer's disease.
Technical Context
ACh is synthesised from choline + acetyl-CoA by choline acetyltransferase (ChAT) and degraded by acetylcholinesterase (AChE). Two receptor types: nicotinic (ligand-gated ion channels — at neuromuscular junction and autonomic ganglia) and muscarinic (GPCRs — M1-M5, in brain, heart, smooth muscle, glands). At the neuromuscular junction (NMJ): ACh release from motor neuron → nicotinic receptor activation on muscle endplate → sodium influx → endplate potential → muscle contraction. In myasthenia gravis, autoantibodies target NMJ components (AChR antibodies in 85%, MuSK antibodies in 5-8%), impairing neuromuscular transmission → fluctuating muscle weakness. Zilucoplan inhibits complement C5, preventing MAC-mediated damage to the postsynaptic membrane that worsens AChR loss. In the brain, cholinergic neurons in the basal forebrain project to the cortex and hippocampus — their degeneration in Alzheimer's disease causes cognitive decline, forming the rationale for cholinesterase inhibitor therapy.