NRS 250 Final - Neurotransmitters

Otto Loewi’s Experiment 

• Otto Loewi stimulated the vagus nerve of a frog heart, which slowed the heart rate. 

• He transferred the solution bathing that heart to a second frog heart. 

• The second heart also slowed, despite no neural connection. 

• This demonstrated that a chemical—later named acetylcholine—was responsible for transmitting signals across the synapse. 

• Loewi's experiment was the first direct evidence of chemical neurotransmission. 

ACh Synthesis 

• ACh is synthesized in the presynaptic terminal from acetyl CoA and choline. 

• The enzyme choline acetyltransferase (ChAT) catalyzes the reaction. 

• ChAT activity is the rate-limiting step of ACh synthesis. 

• ACh is then packaged into synaptic vesicles by the vesicular acetylcholine transporter (VAChT). 

ACh Receptors: Nicotinic and Muscarinic 

• Nicotinic receptors are ionotropic, meaning the receptor is a channel that opens directly when ACh binds. 

• Found in CNS and at neuromuscular junctions. 

• Binding of 2 ACh molecules opens the channel for Na⁺ and K⁺. 

• Net Na⁺ influx leads to depolarization (EPSP). 

• Muscarinic receptors are metabotropic (GPCRs). 

• Found in organs like the heart. 

• Binding of ACh activates G-proteins → beta-gamma subunits open K⁺ channels. 

• K⁺ exits the cell, causing hyperpolarization (IPSP), decreasing heart rate. 

Pharmacology - Nicotinic and Muscarinic

• Nicotinic receptor: 

• Agonist: Nicotine → mimics ACh → EPSPs. 

• Antagonists: Curare and α-bungarotoxin → block ACh binding → no muscle contraction → paralysis. 

• Muscarinic receptor: 

• Agonist: Muscarine (from mushrooms) → causes IPSPs. 

• Antagonist: Atropine → blocks IPSPs, increasing heart activity. 

ACh Inactivation 

• ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE). 

• AChE hydrolyzes ACh into acetate and choline. 

• Choline is taken back up into the presynaptic terminal to be reused in ACh synthesis. 

Neuropeptides 

• Synthesized in the cell body, unlike small molecule neurotransmitters. 

• Packaged into dense core vesicles and transported to the terminal. 

• Released after high-frequency stimulation due to higher Ca²⁺ requirements. 

• Act on metabotropic receptors and have longer-lasting effects. 

Endocannabinoids 

• Not stored in vesicles; synthesized on demand in the postsynaptic neuron. 

• Diffuse retrogradely to act on presynaptic CB1 receptors. 

• Inhibit neurotransmitter release—modulate synaptic transmission. 

• Lipid-based molecules (e.g., anandamide). 

Nitric Oxide (NO) 

• Also synthesized on demand from arginine via nitric oxide synthase (NOS). 

• Not stored in vesicles; diffuses freely across membranes. 

• Acts on guanylyl cyclase in target cells to increase cGMP. 

• Plays a role in vasodilation and synaptic plasticity.