Concepts of neural nitric oxide‐mediated transmission

Abstract

As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short-and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre-and ⁄ or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success.

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

“…In insects and a number of marine invertebrates it has already been demonstrated that NO behaves as an anterograde signal molecule (Bicker, 2001;Palumbo, 2005), similar to vertebrates (Garthwaite, 2008). On the other hand, although the retrograde signal function of NO is well demonstrated in mammalian cortical and hippocampal spiny neurons (Garthwaite, 2008), and in lower vertebrates (Holmqvist and Ekström, 1997), it might be absent in invertebrates (Vincent, 2010), which is also suggested by the present study.…”

“…Nitric oxide (NO) is a prominent gaseous signal molecule playing a particular role in neurotransmission (Garthwaite, 2008). In the nervous system NO is synthetized by the neuronal form of nitric oxide synthase (nNOS), and exerts its effect mainly by inducing cyclic guanosine monophosphate (cGMP) synthesis through the activation of its receptor, soluble guanylate cyclase (sGC), or influences protein activity via S-nitrosylation of defined cysteine residues.…”

“…NO is considered to be a transmitter or modulator acting alone or as a co-transmitter in anterograde way in the cerebral cortex, cerebellum, brainstem, and the peripheral nervous system. It also can be released from the postsynaptic sites of spiny neurons, acting in a retrograde way in the cerebral cortex and hippocampus (Garthwaite, 2008). Because of the physico-chemical properties of NO it is not surprising that NO behaves as a classical neurotransmitter both at the synapses and neural appositions without membrane specializations, moreover, NO is proposed to act also in a different, less target specific way as a volume signal molecule (Garthwaite, 2008;Vincent, 2010).…”

“…It also can be released from the postsynaptic sites of spiny neurons, acting in a retrograde way in the cerebral cortex and hippocampus (Garthwaite, 2008). Because of the physico-chemical properties of NO it is not surprising that NO behaves as a classical neurotransmitter both at the synapses and neural appositions without membrane specializations, moreover, NO is proposed to act also in a different, less target specific way as a volume signal molecule (Garthwaite, 2008;Vincent, 2010). By volume release NO was shown to modulate the rhythmic activity in a broad tissue area, affecting a number of neurons located even far from the release site (Kiss and Vizi, 2001;Philippides et al, 2005;Ott et al, 2007;Münch et al, 2010).…”

Hyperpolarization-Activated Current (I h) in Vestibular Calyx Terminals: Characterization and Role in Shaping Postsynaptic Events

“…cAMP can also shift activation positively by PKA-mediated channel phosphorylation (Liao et al 2010). Our data show that cGMP is a potent modulator of I h , and in vivo cGMP levels could be modulated through nitric oxide activation of guanylyl cyclase (Garthwaite 2008). Dopamine is found in auditory efferents (Gáborján et al 1999), and immunoreactivity for dopamine receptor subtypes D1A and D2L was reported on both inner and outer faces of calyces from the rat saccule and mouse utricle (Drescher et al 2010).…”