Non-Classical Neurotransmission

7/29/2019 Non-Classical Neurotransmission

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Non-classical neurotransmitters

Nitric Oxide

PeptidesATP 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

cerebellum and has been involved in neurotoxicity mediated by NMDA receptors



Non-classical neurotransmitters

Nitric Oxide

Peptides ATP and Adenosine


http://slidepdf.com/reader/full/non-classical-neurotransmission 5/29Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.



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

Peptides co-localize with other

neurotransmitters

Peptides are transported

in vesicles along withprocessing enzymes

as pro-peptides by fast

axonal transport



Nolte J, Integrated Neuroscienc

Peptides use different types of synaptic vesicles and release mechanis



FIGURE 20-4: Neuropeptides and conventional neurotransmitters are released from different parts of the nerve terminal

neuromuscular junction containing both large dense-core vesicles (containing the neuropeptide SCP) and small synaptic vesicle

(containing acetylcholine) was stimulated for 30 min at 12 Hz (3.5 s every 7 s). Depletion of the small clear vesicles at the muscleface and of the peptide granules at the nonmuscle face of the nerve terminal was observed. After stimulation, there was an incre

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 lo

precursor molecules and then cleaved by specific proteases
















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.

G-protein

Neuropeptide Receptors




Function of Neuropeptides: NPY



Role of leptin and hypothalamic peptides in the control of appetit

WT vs. ob/ob



Complex control of appetite involves several hypothalamic peptid

Adapted from Flier, Cell, 116, 342



Non-classical neurotransmitter

Nitric Oxide

PeptidesATP and Adenosine(purinergic neurotransmitters)



Purinergic neurotransmitters: Adenosine and ATP

ATP, ApnA






Purine release and metabolism



Nucleotide degradation and salvage pathway

Lesch-Nyhan syndrome



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, isused clinically to produce coronary vasodilation

ENTs CNTs





A1 agonist binding (3H-CPX)

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 adenosto 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.

A t f ti



A2A immunostaining

A2A is highly expressed in dorsal

striatum, nucleus accumbens and

olfactory tubercle.

In the straitum, A2A , which is couto Gs inhibits D2R action.

D2R is coupled to Gi, therefore A

antagonists are being tested as

potential drugs for the treatment

Parkinson’s disease.

Methylxanthines such as caffeineas antagonists of A2A receptors

A2A receptor function

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



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Non-Classical Neurotransmission