Non-classical neurotransmitters Nitric Oxide Peptides ATP and Adenosine

Nitric Oxide Synthesis and Function

Can NO be consider an unconventional neurotransmitter?

NO acts as a retrograde messenger during LTP in the hippocampus and LTD in the cerebellum and has been involved in neurotoxicity mediated by NMDA receptors

Non-classical neurotransmitters Nitric Oxide

Peptides
ATP and Adenosine

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Peptides are synthesized in the cell body and released from large dense core vesicles

Peptides are transported in vesicles along with processing enzymes as pro-peptides by fast axonal transport

Peptides co-localize with other neurotransmitters

Peptides use different types of synaptic vesicles and release mechanisms

Nolte J, Integrated Neuroscience, 2007

FIGURE 20-4: Neuropeptides and conventional neurotransmitters are released from different parts of the nerve terminal. A neuromuscular junction containing both large dense-core vesicles (containing the neuropeptide SCP) and small synaptic vesicles (containing acetylcholine) was stimulated for 30 min at 12 Hz (3.5 s every 7 s). Depletion of the small clear vesicles at the muscle face and of the peptide granules at the nonmuscle face of the nerve terminal was observed. After stimulation, there was an increase in the number of large dense-core vesicles within one vesicle diameter of the membrane. (Adapted from Karhunen et al., 2001.)

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Biosynthesis of Peptides

Multiple peptides can be derived from the same gene. Peptides are synthesized as long precursor molecules and then cleaved by specific proteases

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Neuropeptide Receptors

G-protein

FIGURE 20-10: Serpentine (seven-transmembrane-domain) receptors for peptides have binding for their peptide ligands within the membrane and in the NH2-terminal loop.
Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Function of Neuropeptides: NPY

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Role of leptin and hypothalamic peptides in the control of appetite

WT vs. ob/ob

Complex control of appetite involves several hypothalamic peptides

Adapted from Flier, Cell, 116, 342 (2004).

Non-classical neurotransmitters Nitric Oxide Peptides

ATP and Adenosine

(purinergic neurotransmitters)

Purinergic neurotransmitters: Adenosine and ATP

ATP, ApnA

Purine release and metabolism

Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

Nucleotide degradation and salvage pathway

Lesch-Nyhan syndrome

ENTs

CNTs

The structure of the different nucleoside transporters is not known but they transport nucleoside analogs that act as therapeutic drugs for the treatment of cancer or AIDS (AZT). Adenosine produces vasodilation and dipyridamole, an inhibitor of adenosine transporter, increases its levels extracellularly and thus, is used clinically to produce coronary vasodilation

A1 is coupled to Gi/o and activation has been implicated in the anxiolytic, anticonvulsant, analgesic and sedative actions of adenosine. Adenosine A1 receptor agonists have being proposed as neuroprotective agents in the treatment of stroke because binding of adenosine to presynaptic A1 receptors inhibits glutamate release while activation of postsynaptic A1 receptors opens K+ and Cl- channels and hyperpolarizes the cell. Also, A1R activation inhibits microglia activation.
A1 agonist binding (3H-CPX)

A2A receptor function

A2A is highly expressed in dorsal striatum, nucleus accumbens and olfactory tubercle. In the straitum, A2A , which is coupled to Gs inhibits D2R action. D2R is coupled to Gi, therefore A2A antagonists are being tested as potential drugs for the treatment of Parkinsons disease.
A2A immunostaining

Methylxanthines such as caffeine, act as antagonists of A2A receptors

A2B receptors are present in endothelial cells, where they regulate vascular permeability. Both A2A and A2B receptors contribute to vasodilation.

Different role of purinergic receptors in synaptic plasticity