Nitroxigenic transmission Flashcards
Criteria to be classified as an NT
On demand synthesis
Stored in synaptic vesicles
released by exocytosis
Actions at receptors
an inactivation/reuptake mechanism
Properties of NO
A gas and a free radical (highly reactive: labile)
There is no storage
It diffuses from site of production - short range transmission with no receptors
Membrane permeable
Short half life - metabolised by superoxide
As such not classified as a NT, however some argue it is due to its localisation exhibited by immunolocalisation (determined with antibodies).
Isoforms of NO synthase and synthesis of NO
nNOS (neuronal)
iNOS (inducible)
eNOS (endothelial)
mtNOS (mitochondrial ?? not much known)
L-arginine + O2 -> citrulline + NO, catalysed by NOS
Ca2+ and calmodulin needed for synthesis (except for iNOS)
Electron donors also involved, e.g., NADPH and tetrahydrobiopterin. As such has been seen co-localised with NADPH in cells.
NO signalling targets and effects in the PNS
Primarily acts on soluble guanylyl cyclase, which increases cGMP. This activates PKG, decreases IC [Ca], and inhibits PDE.
NO can also bind to non-heme irons, and S-nitrosylate proteins
In the periphery, NO mediates smooth muscle relaxation (primarily in vasculature).
Also mediates vasodilatation in the salivary glands - study saw NOS inhibitors blocked vasodilatation, while NO donors and PDE inhibitors increased relaxation.
nNOS-mediated signalling
Excess can be toxic. Linked to NMDA signalling.
Regulates excitability, LTP, firing rate, depression, learning/memory, and NT release.
nNOS is located in the pyloric sphincter and penile nerves, and mediates dilatation of the stomach/sphincter and erections (mediated by vasodilatation)
nNOS dilates urinary bladder, trachea, and portal vein.
Co-transmission of NO
In the portal vein it was found to be cotransmitted with ATP, with ATP synergistically mediating the vasodilatation with NO.
Co-transmission with ACh in the salivary glands.
VIP cotransmission in myenteric neurones (also with carbon monoxide), eyes, salivary glands, and cerebral arteries.
Glutamate and GABA cotransmission in cerebellum
ChAT in brainstem
and somatostatin and NPY in corpus striatum
Carbon monoxide biosynthesis (and enzyme), and physiological effect
Long halflife.
Formed by heme oxygenase (HO) by oxidising the heme ring to form CO and other side products (Fe + bilverdin), with NADPH-CYP reductase required.
Has 3 isoforms: HO1 induced by cellular stress, HO2 and HO3 are constitutive - they are constantly active/present.
CO has been found to inhibit HO and to activate soluble gunaylyl cyclase (less so than NO tho).
in myenteric neurones it is seen to be colocalised with nNOS.
