Neuroscience/Objectives/Lecture 5

From PhysioWiki

Neurotransmitters

Indicate what criteria a molecule must fulfill to be a neurotransmitter.

Must:

• be synthesized in a neuron
• be found at the presynaptic terminal
• be released in sufficient amounts to exert an effect on the postsynaptic neuron or effector organ
• mimic the action of endogenously released transmitter when applied exogenously
• be inactivated quickly via a specific mechanism (uptake or degradation)

Describe the 5 major steps involved in chemical synaptic transmission (eg, synthesis, storage, release, receptor binding, inactivation).

De novo synthesis of neurotransmitters occurs in the soma; some neurotransmitters may also be recycled and reconstituted in the presynaptic bouton.

Neurotransmitters are packaged into vesicles and stored at the presynaptic terminal, where they await their release.

Release is dependent upon action potentials. Arrival of an action potential at the presynaptic terminal opens calcium channels, resulting in presynaptic calcium influx. Calcium causes vesicles to fuse with the presynaptic membrane, releasing neurotransmitters into the synaptic cleft.

Neurotransmitters diffuse across the synaptic cleft and bind to specific receptors. Postsynaptic receptors may be ionotropic or metabotropic, and may have excitatory or inhibitory effects. Presynaptic receptors (autoreceptors) often have inhibitory effects to downregulate the amount of neurotransmitter released by the presynaptic neuron. This allows neurons to maintain homeostatis.

Inactivation of neurotransmitters proceeds via reuptake into the presynaptic terminal, enzymatic degradation, or diffusion. A neurotransmitter's inactivation may be governed by one or more of these mechanisms. For example, serotonin is inactivated both by reuptake and by enzymatic degradation. On the other hand, nitric oxide (NO) is inactivated by simple diffusion.

List the major neurotransmitters and DEFINE their classification based upon their chemical structure.

The biogenic amines are very small molecules and include acetylcholine (ACh), serotonin (5-HT), histamine, dopamine (DA), norepinephrine (NE), and epinephrine (Epi). Their structures are common in that they all possess amino functional groups.

Amino acid neurotransmitters are also small and include GABA, glutamate, and glycine. These molecules have structures common to all amino acids (carbon stereocenter with hydrogen, amine, carboxylic acid, and R group).

The peptide neurotransmitters are larger molecules and include enkephalins, dynorphin, substance P, neuropeptide Y, and many others. Their structural commonality is that they are all composed of two or more amino acids.

Describe the rate-limiting steps and the principal precursors required for the synthesis of ACh, catecholamines (DA, NE, Epi), 5-HT, glutamate, and GABA.

Describe the enyzmatic degradative pathways involved in the termination of neurotransmitter activity (eg, MAO, COMT, GABA-T).

In addition to reuptake mechanisms, catecholamines can be inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

GABA can be degraded by GABA-T to form succinic semialdehyde as long as α-ketoglutarate is the amine group acceptor.

ACh can be degraded into choline and acetate by acetylcholinesterase found on the postsynaptic membrane.

Describe the inactivation of neurotransmitter action by cellular uptake mechanisms and DISCUSS the mechanism of action of antidepressant drugs and CNS stimulants.

5-HT has behavioral effects related to mood. Extending the time of action of 5-HT can relieve depression. This can be achieved either by removing enzymatic degradation or by blocking reuptake proteins.

Describe the synthesis and release of peptide neurotransmitters (e.g. opioid peptides).

Neurotransmitters are coded for by DNA, which is transcribed to mRNA in the nucleus. The mRNA contains a signal sequence that targets it to the rough endoplasmic reticulum, targeting the Golgi for packaging into vesicles. The mRNA is then translated into a pre-propeptide and the signal peptide is removed within the RER. After vesicular packaging, specific enzymes convert the propeptide into a biologically active peptide.

There are no reuptake processes for neuropeptide. Upon release, they are generally degraded by proteases in the synaptic cleft.

Identify major nuclei in the CNS with high concentrations of selective neurotransmitters (e.g. ACh, DA, NE, 5-HT, histamine).