Acetylcholine · Grey Matter

Acetylcholine is the transmitter that makes muscles contract at the neuromuscular junction and, inside the brain, a neuromodulator of attention, arousal and learning released from the basal forebrain and brainstem.

Acetylcholine. Acetylcholine is the transmitter that makes muscles contract at the neuromuscular junction and, inside the brain, a neuromodulator of attention, arousal and learning released from the basal forebrain and brainstem.

It works on two receptor families. Nicotinic receptors are ionotropic channels for sodium and potassium (some brain types pass calcium too), and they give the fast, reliable excitation of skeletal muscle; muscarinic receptors are metabotropic, and in the brain they mostly close potassium channels and make neurons more excitable for seconds. Acetylcholine is the only classical transmitter cleared by an enzyme in the cleft: acetylcholinesterase splits it in about a millisecond, and the choline is taken back to make more.

In the cortex it favours input over recall. Cholinergic neurons of the nucleus basalis project across the cortex and are active in attentive waking and in REM sleep; acetylcholine strengthens responses to incoming sensory signals relative to internal, recurrent activity, which is one account of its role in attention and encoding.

At the muscle it is generous. One motor nerve spike releases dozens of vesicles, each with thousands of acetylcholine molecules, far more than needed to fire the muscle fibre, a safety margin that diseases such as myasthenia gravis erode.

Many drugs target it. Nicotine acts on nicotinic receptors; atropine blocks muscarinic ones; cholinesterase inhibitors raise acetylcholine in myasthenia gravis and, modestly, in Alzheimer's disease, where cholinergic neurons degenerate early.

Acetylcholine is the same molecule doing two jobs at two speeds.

Through nicotinic channels it fires muscles in milliseconds; through muscarinic receptors it tells the cortex to pay attention for seconds.

Questions: How can acetylcholine act both in milliseconds and over seconds? It has two receptor families. Nicotinic receptors are ion channels, so acetylcholine opens them within a millisecond; at the neuromuscular junction this fires every muscle fibre the motor neuron reaches. Muscarinic receptors are coupled to G proteins, so their effects start more slowly and last seconds; in the cortex they mostly close potassium channels and make neurons more excitable. Acetylcholinesterase in the cleft ends the fast signal within about a millisecond, which keeps neuromuscular transmission sharp, while in the brain the slower muscarinic actions shape attention and arousal. What does acetylcholine from the basal forebrain do to the cortex? Cholinergic neurons of the nucleus basalis and nearby basal forebrain project across the cortex and are most active in attentive waking and in REM sleep. Their acetylcholine makes cortical neurons more excitable and, in many studies, boosts responses carried by incoming sensory pathways relative to activity from recurrent connections within the cortex. One account is that this tilts the cortex toward taking in new information and encoding it, rather than recalling what it already holds. Loss of these neurons early in Alzheimer's disease is one reason cholinesterase inhibitors give a modest benefit there. Why does botulinum toxin paralyse muscles while tetanus toxin makes them rigid? Both toxins are enzymes that cut SNARE proteins, and without intact SNAREs vesicles cannot fuse. Botulinum toxins act on motor nerve terminals at the neuromuscular junction, so acetylcholine release stops and the muscle goes limp; that is also how cosmetic and medical botulinum injections relax a chosen muscle. Tetanus toxin is carried backward up the motor axon into the spinal cord, where it cuts synaptobrevin in the inhibitory interneurons that release glycine and GABA onto motor neurons. With that brake gone the motor neurons fire unchecked and the muscles lock in spasm, so the same molecular cut gives opposite symptoms depending on which synapse loses it.