Nitric oxide (and carbon monoxide) [gas "transmitters"]

In 1998, the Nobel Prize in Physiology and Medicine was awarded jointly to: ROBERT F. FURCHGOTT, LOUIS J. IGNARRO and FERID MURAD for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system.

TRANSPARENCY (from Snyder, 1992)
NO (nitric oxide, not nitrous oxide = laughing gas)
arginine is converted by NOS to NO and citrulline
diffuses to next cell, no vesicles or release mechanism
EDRF=endothelial derived relaxation factor, mediates vasodilation -corpus cavernosum
mediates penile erection via the parasympathetic nervous system
(Viagra blocks an enzyme that interferes with NO's effect.)
stimulates G-cyclase
lipophilic, crosses membranes
very unstable, so no breakdown mechanism needed
no breakdown, so synthesis should be carefully controlled
TRANSPARENCY (from Barinaga)
CO - derived from heme by heme oxygenase to stimulate guanylyl cyclase

Nitric oxide (NO) - Nitric oxide synthase (NOS) domains:
TRANSPARENCY (Fig. 1, Brenman & Bredt, 1997)
[1] N-terminal 1-498 amino acids of iNOS is oxygenase
binds heme (iron protoporphyrin IX, tetrahydrobiopterin and substrate (L-Arg)
binding the latter 2 cause enzyme to dimerize
[2] CaM binding - amino acids 499-530, thus Ca2+ regulates
[3] amino acids 531-1144
binds FMN (flavin adenine mononucleotide), FAD (FA dinucleotide), NADPH


There are (at least) 3 kinds (the first and third are constitutive):
(1) eNOS (endothelial) [recall that NO was originally called EDRF=endothelial derived relaxation factor
(2) iNOS (inducible by cytokines) for defensive cytotoxin production by macrophages
and
(3) nNOS neuronal (where a muscle form, nNOSm [mu] has an exon spliced between CaM & FMN
nNOS has PDZ domain near N-terminal

muscle:
nNOS is linked to dystrophin complex (specifically to PDZ domain on syntrophin)
developmentally, involved in myoblast fusion

neurons:
PDZ links to NMDA glutamate receptors via PSD-95 (and PSD-93)
TRANSPARENCY (Fig. 2, Brenman & Bredt, 1997)
P = postsynaptic density (PSD-25) [rat]
D = disc-large (dlg) [Drosophila]
Z = zonula occludentes-1 [mouse]
PSD=postsynaptic density, has 3 PDZ domains
NMDA implicated in neurotoxicity and LTP=long term potentiation
PDZ domains bind to PDZ domains or short amino acid consensus sequences

recent structural studies - unusual in that heme is exposed,
(originally, researchers expected that it would be like cytochrome P-450 with heme in pocket)
TRANSPARENCY Fig. 1 Crane et al.

References:

J. E. Brenman & D. S. Bredt, Synaptic signalling by nitric oxide, Current Opinion in Neurobiology 1997, 7, 374-378.

D. E. Koshland, Jr., The molecule of the year (Editorial) Science 258, 1861, 1992. Also: NO news is good news (Molecule of the year) pp. 1862-1863.

S. H. Snyder, Nitric oxide: First in a new class of neurotransmitters? (Perspectives) Science 257, 1992, 494 - 496.

M. Barinaga, Carbon monoxide: Killer to brain messenger in one step (Research News Neuroscience) Science 259, 309, 1993

I. Wickelgren, Biologists catch their first detailed look at NO enzyme (Research news, structural biology) Science 278, 389, 1997

B. R. Crane et al., The structure of nitric oxide synthase oxygenase domain and inhibitor complexes. Science 278, 425-431, 1997

This page last revised on December 19, 2001

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