Acetylcholine
Acetylcholine (ACh) is a common neurotransmitter secreted by a variety of neurons.
It binds to two different receptors - Ionotropic (fast) nicotinic receptors and metabotropic (slow) muscarinic receptors.
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- agonists and antagonists
- anticholinergic effetcs
- role of acetylcholine in disease
Role in Central Nervous System
Acetylcholine is restricted in the CNS, being limited to:
- basal forebrain complex, innervating hippocampus and all of cortex
- parts of the reticular formation
- pontomesencephalotegmental cholinergic complex - innervates dorsal thalamus and parts of forebrain
- likely involved in arousal, sleep-wake cycles, and perhaps learning and memory
- Alzhemier's diease patients show a significant loss of acetylcholine in the cortex and hippocampus and corresponding loss of cells from the basal nucleus
Role in the Peripheral Nervous System
- Preganglionic neurons of the autonomic nervous system, both the SNS and the PNS, secrete ACh, where its binds to ionotropic nicotinic receptors.
- Postganglionic neurons of the vagus nerve act on metabotropic muscarinic receptors of cardiac cells to reduce heart rate
- Postganglionic PNS neurons secrete ACh at synapses with cardiac and smooth muscle and glands, where it binds to .
- Somatic neurons secrete ACh at the neuro-muscular junction, where it binds nicotinic receptors.
- Some postganglionic SNS neurons express ACh at sweat glands, where it binds muscarinic receptors.
Receptors and Signaling
ACh is made in the pre-synaptic terminal by choline acetyltransferase and is stored and released from vesicles, each which contains 6000-10,000 ACh molecules.
- ionotropic ACh receptors undergo conformational change upon ACh binding, inducing cation influx
- metabotropic receptors activate a-GTP and βγ subunit, which activates K channels, inducing K influx and cell hyperpolarization
ACh is primaily removed form the synapse by the action of acetylcholineesterase (AChE)
Agonists and Antagonists
- botulinum and tetanus toxins inhibit ACh vesicle release
Agonists
- carbachol (muscarinic)
- succinylcholine binds for prolonged time, leading to secondrary relaxation and flaccid paralysis
- nicotine
AChE inhibitors (reversible)
- donepezil (Aricept) (used in AD)
- neostigmine (used in myesthenia gravis)
AChE inhibitors (irreversible)
- malathion - insecticide
- nerve gas - sarin
Antagonists
- atropine (muscarinic)
- curare (nicotinic)
- benztropine
Anticholinergic Effects
anticholinergic effects can cause dry mouth, constipation, blurry vision, delerium, cognitive impairment, etc
- paroxetine is quite strongly anticholinergic
- low potency antipsychotics
Role in Disease
- in myesthenia gravis, antibodies against the AChR form, usually following thymus hyperplasia.