Chemical transmission

 Synapses 

I.               Structural features/components of the nerve terminal 

a.     Presynaptic membrane is not homogenous—contains specialized regions of neurotransmitter (NT) release called active zones 

b.     Vesicles containing NT are located near active zones within the presynaptic terminal 

i.        Vesicles provide protection against NT degradation within the neuron  Each vesicle contains the same amount of NT, so stronger signals can be coded for by releasing more vesicles 

ii.      As an AP propagates to the synaptic terminal, the probability of vesicle docking and fusion with the membrane increases 

1. Docking is Ca2+ sensitive (increases with increases in Ca2+) but is NOT 

Ca2+ dependent 

iii.     SNARES are scaffold proteins and are the Ca2+ sensitive machinery that facilitates vesicle docking at the active zones  

iv.     Fusion of vesicles, which allows NT release, IS Ca2+ dependent 

c.     Voltage-sensitive Ca2+ channels, especially clustered near active zones 

i.        Clustering of these channels creates a microdomain of Ca2+ influx  ii. Similar to the Na+ and K+ channels we’ve discussed so far, these channels are voltage-gated AND selective for only Ca2+ 

iii. ECa is high around +120mV due to the high ratio of extracellular to intracellular Ca2+ (10,000:1), so there is still a large driving force for Ca2+ even when the membrane is depolarized to ~40mV as it may be during an AP 

d.     Abundant mitochondria to provide energy for neurotransmitter release 

II.             Neurotransmitters 

a.     Single amino acids (most common) 

i.        Glutamate—excitatory  ii. GABA (a decarboxylated form of glutamate)—inhibitory   iii. Glycine—often inhibitory 

b.     Biogenic amines/monoamines 

i.        Norepinephrine (NE) Involved in arousal, learning, and attention

ii.      Serotonin (5-HT) , Involved in mood regulation

iii.     Acetylcholine (Ach),  Involve din learning, memory, sleep, and motor function iv. Dopamine (DA), Involved in reward processing and motor function v. Histamine, involved in immune responses, gastric function, and neurotransmission. vi. Epinephrine (Adrenaline): A neurotransmitter that prepares the body for quick responses to stress.

c.     Neuropeptides 

i.        e.g. Substance P (transmission of pain) , vasopressin  (vasopressin's primary function is to regulate the body's water balance by promoting water reabsorption in the kidney. It also plays a role in pair bonding controlling monogamy). There are many neuropeptides. These are just 2 examples

III.           Neurotransmitter release 

i. As an AP propagates to the synaptic terminal, the probability of vesicle docking with the membrane increases 

1. Docking is Ca2+ sensitive (increases with increases in Ca2+) 

ii.  SNARES are scaffold proteins and are the Ca2+ sensitive machinery that 

                                    facilitates vesicle docking at the active zones  

iii.                  Fusion of vesicles to the active zone membrane allows NT release into the synapse  iv. Fusion of vesicles, which allows NT release, IS Ca2+ dependent 

v. Once NT has been released into the synapse there is … 

1.     Activation of post-synaptic receptors (which is the whole reason for having synaptic transmission) 

2.     A need to remove NT from the synapse, so that post-synaptic signaling only occurs when the pre-synaptic cell fires an AP 

NT degrading enzymes, re-uptake of NT by the pre-synaptic cell, diffusion away from the synapse 

            Ionotropic and Metabotropic Receptors 

I.               Neurotransmitter receptor functions 

a.              Binding of neurotransmitter (ligand) 

i.    Receptors show high specificity for their NT   ii. Agonists mimic the activity of the native ligand  iii. Antagonists block the activity of the native ligand 

II.             Types of receptors  

a.              Ionotropic receptors are neurotransmitter-gated ion channels  

                              i.     Structure/Binding (e.g. AMPA receptor) 

1.     Glutamate binding to the extracellular surface of receptor permits opening of the channel allowing permeable ions to flow through 

2.     What ions will flow through an AMPA receptor at rest?  Will this lead to an EPSP or IPSP? 

ii.      Effector action (e.g. AMPA receptor) 

1.     Binding of glutamate (ligand) to the receptor will lead to the opening of the ion channel pore, in the case of AMPA receptors, the channel is selective for cations (note that most NT gated ion channels are not specific for a single ion, but rather a class of ions) 

2.     This general mechanism is true for all NT-gated receptors, regardless of the number and type of subunits and independent of cation vs. anion selectivity 

This receptor is selective for Na and K; however, since the cell at rest is at -65 mV, the Na+ current plays a more significant role in the postsynaptic response leading to an Excitatory Postsynaptic Potential (EPSP, depolarization)

This happens because Na is very far away from its equilibrium potential (+60 mV); therefore, a lot of Na+ flows into the cell through AMPA receptors.

3.     Another example is the GABAa receptor, which is selective for Cl. When GABA binds the GABAa receptor, there is an inhibitor postsynaptic potential in the post-synaptic cell (IPSP, hyperpolarization)

iii.     Summary 

1.     Ionotropic receptors are ligand (or NT)-gated ion channels  

2.     They can be excitatory or inhibitory 

3.     Type of response depends on the NT involved and the type of channel 

4.     Ionotropic receptors allow for extremely fast signaling 

b.              Metabotropic receptors

They are NOT ion channels

Metabotropic receptors are a type of cell surface receptor that, when activated by a ligand (such as a neurotransmitter), initiate a signaling cascade through intracellular second messengers rather than forming an ion channel like ionotropic receptors. These receptors are typically G protein-coupled receptors (GPCRs) and play a crucial role in various physiological processes by modulating neuronal excitability and influencing various cellular responses.

There are many types of metabotropic receptors, each with different ligands and signaling pathways, including neurotransmitter receptors like muscarinic acetylcholine receptors and noradrenergic receptors.